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Yu Z, Sun Y, Guo C. Evaluating pretreatment serum CA-125 levels as prognostic biomarkers in endometrial cancer: a comprehensive meta-analysis. Front Oncol 2024; 14:1442814. [PMID: 39399178 PMCID: PMC11466722 DOI: 10.3389/fonc.2024.1442814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 08/28/2024] [Indexed: 10/15/2024] Open
Abstract
Background In recent years, the incidence of endometrial cancer (EC) has been rising. This meta-analysis aims to clarify the prognostic significance of serum CA-125 levels in EC. Methods Articles up to March 1, 2024, were systematically searched in EMBASE, Cochrane Library, PubMed, and Web of Science. This analysis pooled hazard ratios (HR) and 95% confidence intervals (CI) from qualifying studies to evaluate the association of CA-125 levels with overall survival (OS), progression-free survival (PFS), disease-free/relapse-free survival (DFS/RFS), and disease-specific survival (DSS). Results 25 studies involving 7,716 patients were included. The analysis revealed that elevated CA-125 levels correlate with poorer OS (HR = 1.848, 95% CI: 1.571-2.175, p < 0.001). This association persisted across various study regions and sample sizes, and was notably strong in subgroups with a CA-125 cut-off value of less than 35 (HR = 2.07, 95% CI: 1.13-3.80, p = 0.019) and equal to 35 (HR = 2.04, 95% CI: 1.49-2.79, p < 0.001), and among type II pathology patients (HR = 1.72, 95% CI: 1.07-2.77, p = 0.025). Similarly, high CA-125 levels were linked to reduced PFS, particularly in subgroups with a CA-125 cut-off value less than 35 (HR = 1.87, 95% CI: 1.15-3.04, p = 0.012) and equal to 35 (HR = 4.94, 95% CI: 2.56-9.54, p < 0.001), and in endometrioid endometrial cancer patients (HR = 2.28, 95% CI: 1.18-4.40, p = 0.014). Elevated CA-125 levels were also indicative of worse DFS/RFS (HR = 2.17, 95% CI: 1.444-3.262, p < 0.001) and DSS (HR = 2.854; 95% CI: 1.970-4.133, p < 0.001). Conclusion Serum CA-125 levels before treatment was highly associated with prognosis of EC patients.
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Affiliation(s)
| | | | - Cuishan Guo
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical
University, Shenyang, Liaoning, China
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Hegde S, Wagh K, Narayana SM, Abikar A, Nambiar S, Ananthamurthy S, Narayana NH, Reddihalli PV, Chandraiah S, Ranganathan P. microRNA profile of endometrial cancer from Indian patients-identification of potential biomarkers for prognosis. Biochem Biophys Rep 2024; 39:101812. [PMID: 39282095 PMCID: PMC11395764 DOI: 10.1016/j.bbrep.2024.101812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 08/15/2024] [Accepted: 08/16/2024] [Indexed: 09/18/2024] Open
Abstract
Endometrial cancer is one of the major cancers in women throughout the world. If diagnosed early, these cancers are treatable and the prognosis is usually good. However, one major problem in treating endometrial cancer is accurate diagnosis and staging. Till date, the choice method for diagnosis and staging is histopathology. Although there are few molecular markers identified, they are not always sufficient in making accurate diagnosis and deciding on therapeutic strategy. As a result, very often patients are under treated or over treated. In this study, our group has profiled microRNAs from Indian patients using NGS-based approach. We have identified 212 differentially expressed microRNAs in endometrial cancer. Among these, there are 17 novel miRNAs. Since this data represents only Indian cohort and also lacks survival data, validation across other populations is necessary before being considered as biomarkers. As one approach towards this, these microRNAs have also been compared to data from TCGA, which represent other populations and also correlated to relevance in overall survival. Using in-silico approaches, mRNA targets of the miRNAs have been predicted. After comparing with TCGA, we have identified 16 miRNA-mRNA pairs which could be potential prognostic biomarkers for endometrial cancer. This is the first miRNA profiling report from Indian cohort and one of the very few studies which have identified potential biomarkers of prognosis in endometrial cancer.
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Affiliation(s)
| | | | | | - Apoorva Abikar
- Centre for Human Genetics, Bengaluru, India
- Manipal Academy for Higher Education, Manipal, India
| | | | | | | | | | - Savitha Chandraiah
- Vani Vilas Hospital, Bangalore Medical College and Research Institute, Bengaluru, India
| | - Prathibha Ranganathan
- Centre for Human Genetics, Bengaluru, India
- Manipal Academy for Higher Education, Manipal, India
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Han LN, Han YW, Yan P. Prognostic values of human epididymis protein 4 expression in patients with endometrial cancer: A systematic review and meta-analysis. J Obstet Gynaecol Res 2022; 48:2255-2269. [PMID: 35844088 DOI: 10.1111/jog.15356] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/06/2022] [Accepted: 06/26/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND There is no consensus on the correlation between human epididymis protein 4 (HE4) and prognosis of endometrial cancer (EC). Therefore, we performed a meta-analysis to assess the relationship between HE4 and prognosis of EC. METHODS In this systematic review and meta-analysis, the databases were searched. Correlation of serum or tissue HE4 with clinicopathological characteristics was determined by odds ratio (OR) or standardized mean difference (SMD) with 95% confidence interval (CI), respectively. The hazard ratio (HR) with 95% CI was calculated to evaluate the correlation between HE4 and survival outcome. RESULTS A total of 38 published studies were eligible. We found that high levels of serum HE4 were associated with FIGO III-IV stage (SMD = 1.58, 95%CI: 1.18-1.98, p < 0.001), grade 3 (SMD = 0.66, 95%CI: 0.39-0.93, p = 0.001), ≥50% myometrial invasion (SMD = 0.78, 95%CI: 0.58-0.99, p < 0.001), lymphovascular space invasion (SMD = 0.82, 95%CI: 0.54-1.11, p = 0.001), lymph node metastasis (SMD = 1.27, 95%CI: 0.84-1.69, p < 0.001), cervical involvement (SMD = 0.71, 95%CI: 0.43-0.98, p = 0.003), parametrial involvement (SMD = 1.03, 95%CI: 0.71-1.35, p < 0.001) and peritoneal cytology (SMD = 0.49, 95%CI: 0.22-0.75, p < 0.001). High expression of tissue HE4 was only significantly associated with lymph node metastasis (OR = 6.19, 95%CI: 2.07-18.50, p = 0.001). High levels of serum HE4 were significantly associated with poor overall survival (univariate: HR = 3.77, 95%CI: 1.94-7.32, p < 0.001; multivariate: HR = 2.15, 95%CI: 1.65-2.80, p < 0.001) and disease-free survival (univariate: HR = 2.89, 95%CI: 2.14-3.88, p < 0.001; multivariate: HR = 2.31, 95%CI:1.20-2.67, p < 0.001) in EC. Compared with cancer antigen 125, serum HE4 may be a better prognostic indicator for EC. CONCLUSIONS High HE4 expression is associated with poor prognosis of EC and may be a potential prognostic biomarker for EC.
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Affiliation(s)
- Li-Na Han
- Department of Obstetrics and Gynecology, Hebei General Hospital, Shijiazhuang, China.,Graduate School of Hebei Medical University, Shijiazhuang, China
| | - Yi-Wei Han
- Department of Obstetrics and Gynecology, Hebei General Hospital, Shijiazhuang, China.,Graduate School of Hebei Medical University, Shijiazhuang, China
| | - Ping Yan
- Department of Obstetrics and Gynecology, Hebei General Hospital, Shijiazhuang, China
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Hwang WY, Suh DH, Kim K, Kim YB, No JH. Serum Human Epididymis Protein 4 as a Prognostic Marker in Cervical Cancer. Cancer Control 2022; 29:10732748221097778. [PMID: 35506739 PMCID: PMC9072869 DOI: 10.1177/10732748221097778] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 03/14/2022] [Accepted: 04/08/2022] [Indexed: 12/09/2022] Open
Abstract
OBJECTIVES The objective is to evaluate the prognostic value of serum human epididymis protein 4 (HE4) as a tumor marker in patients with cervical cancer. METHODS Sixty-seven patients with cervical cancer treated at Seoul National University Bundang Hospital from September 2014 to May 2018 were retrospectively reviewed. Serum HE4 levels were measured by immunoassay before starting primary treatment. A mean serum HE4 level of 72.6 pmol/L was used to divide the patients into low and high HE4 groups. Patient characteristics, clinicopathological variables, and survival outcomes were compared between the two groups. RESULTS The low and high HE4 groups included 55 (82.1%) and 12 (17.9%) patients at diagnosis, respectively. Higher HE4 levels were significantly associated with older age at diagnosis (age <50: .0% vs age ≥50: 100.0%; P = .002), menopause (premenopause: 8.3% vs postmenopause: 91.7%; P = .009), higher FIGO stage (stage I-II: 33.3% vs III-IV: 66.7%; P = .017), large tumor size (<4.0 cm: 41.7% vs ≥4.0 cm: 58.3%; P = .029), positive lymph node metastasis (negative: 41.7% vs positive: 58.3%; P = .049), and involvement of the parametrium (negative: 25.0% vs positive: 75.0%; P = .002). Higher HE4 level was a predictive factor for worse overall survival but not for progression-free survival. Elevated HE4 levels were not independent factors for the prediction of either overall survival or progression-free survival. Subgroup analysis by histological type revealed similar results for patients with squamous cell carcinoma. CONCLUSIONS High levels of HE4 expression correlated with poor overall survival, indicating that elevated HE4 levels are associated with a poor prognosis for patients with cervical cancer.
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Affiliation(s)
- Woo Yeon Hwang
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Dong Hoon Suh
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Kidong Kim
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yong Beom Kim
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jae Hong No
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
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Yaari Z, Yang Y, Apfelbaum E, Cupo C, Settle AH, Cullen Q, Cai W, Roche KL, Levine DA, Fleisher M, Ramanathan L, Zheng M, Jagota A, Heller DA. A perception-based nanosensor platform to detect cancer biomarkers. SCIENCE ADVANCES 2021; 7:eabj0852. [PMID: 34797711 PMCID: PMC8604403 DOI: 10.1126/sciadv.abj0852] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 09/14/2021] [Indexed: 05/15/2023]
Abstract
Conventional molecular recognition elements, such as antibodies, present issues for developing biomolecular assays for use in certain technologies, such as implantable devices. Additionally, antibody development and use, especially for highly multiplexed applications, can be slow and costly. We developed a perception-based platform based on an optical nanosensor array that leverages machine learning algorithms to detect multiple protein biomarkers in biofluids. We demonstrated this platform in gynecologic cancers, often diagnosed at advanced stages, leading to low survival rates. We investigated the detection of protein biomarkers in uterine lavage samples, which are enriched with certain cancer markers compared to blood. We found that the method enables the simultaneous detection of multiple biomarkers in patient samples, with F1-scores of ~0.95 in uterine lavage samples from patients with cancer. This work demonstrates the potential of perception-based systems for the development of multiplexed sensors of disease biomarkers without the need for specific molecular recognition elements.
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Affiliation(s)
- Zvi Yaari
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
| | - Yoona Yang
- Lehigh University, Bethlehem, PA 18015, USA
| | - Elana Apfelbaum
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
| | - Christian Cupo
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
| | - Alex H. Settle
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
| | - Quinlan Cullen
- Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
| | - Winson Cai
- Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
| | - Kara Long Roche
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
| | | | - Martin Fleisher
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
| | | | - Ming Zheng
- National Institute of Standards and Technology, Gaithersburg, MD 20899, USA
| | | | - Daniel A. Heller
- Memorial Sloan Kettering Cancer Center, NY, New York 10065, USA
- Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
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Quan Q, Liao Q, Yin W, Zhou S, Gong S, Mu X. Serum HE4 and CA125 combined to predict and monitor recurrence of type II endometrial carcinoma. Sci Rep 2021; 11:21694. [PMID: 34737393 PMCID: PMC8569215 DOI: 10.1038/s41598-021-01263-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 10/25/2021] [Indexed: 12/02/2022] Open
Abstract
There is no recognized serum biomarker to predict the recurrence of endometrial carcinoma (EC). We aimed to explore serum human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) as the biomarkers to predict and monitor recurrence of type II EC. 191 patients diagnosed with type II EC were involved for this retrospective study. Comparing recurrent with non-recurrent patients, HE4 levels resulted a statistically significant difference at primary diagnosis and recurrence, respectively (P = 0.002 and P = < 0.001), while CA125 levels resulted statistically significant (P = < 0.001) at recurrence. According to receiver operating characteristic curve analysis, the areas under the curve were significant for HE4 levels at primary diagnosis and recurrence predicting recurrence. Furthermore, CA125 levels at recurrence were significant. And the combination of both markers showed the higher sensitivity and specificity than single one. Patients with higher HE4 levels were associated with worse disease-free survival and overall survival, the opposite was true for patients with lower HE4 levels. The preoperative HE4 levels could be used to evaluate the risk factors of type II EC. Which suggested that HE4 levels might associated with the prognosis of type II EC. And combination of HE4 and CA125 could be applied to monitor recurrence during follow-up.
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Affiliation(s)
- Quan Quan
- Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, China
| | - Qianqian Liao
- Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children, Chongqing, China
| | - Wanchun Yin
- Department of Gynecology, The First People's Hospital of Chongqing Liangjiang New Area, Chongqing, China
| | - Shuwei Zhou
- Department of Obstetrics, Chongqing Health Center for Women and Children, Chongqing, China
| | - Sainan Gong
- Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, China
| | - Xiaoling Mu
- Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, China.
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HE4 as a Biomarker for Endometrial Cancer. Cancers (Basel) 2021; 13:cancers13194764. [PMID: 34638250 PMCID: PMC8507549 DOI: 10.3390/cancers13194764] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/10/2021] [Accepted: 09/17/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary There are currently no blood biomarkers approved for routine clinical use in endometrial cancer. Serum human epididymis protein 4 (HE4) is significantly higher in patients with endometrial cancer compared to patients without endometrial cancer and is associated with a poorer prognosis. This makes HE4 an attractive candidate for clinical use in endometrial cancer. The aim of this review is to summarise the evidence for the use of serum HE4 in the detection, prognosis, prediction of therapy response and recurrence monitoring in endometrial cancer. The utility of combining HE4 with other biomarkers or imaging and clinical variables, and its detection in other biofluids is also discussed, as well as potential challenges for clinical use and recommended areas for future research. Abstract There are currently no blood biomarkers in routine clinical use in endometrial carcinoma (EC). Human epididymis protein 4 (HE4) is a glycoprotein that is overexpressed in the serum of patients with EC, making it a good candidate for use as a diagnostic and/or prognostic biomarker. HE4 is correlated with poor prognostic factors, including stage, myometrial invasion and lymph node metastases, which means it could be used to guide decisions regarding the extent of surgery and need for adjuvant therapy. Serum HE4 has also shown promise for predicting responses to progestin therapy in early-stage EC. The use of algorithms and indices incorporating serum HE4 and other biomarkers, including clinical and imaging variables, is an area of increasing interest. Serum HE4 levels rise with age and renal dysfunction, which may affect the interpretation of results. This review covers the evidence supporting the use of HE4 as an EC biomarker for diagnosis, prognosis, recurrence monitoring, and prediction of therapy response. The evidence for combining serum HE4 with other biomarkers, including clinical and imaging variables, its value as a biomarker in other biofluids and potential challenges of its clinical use are also discussed.
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Azim SA, Mutz-Dehbalaie I, Wieser V, Berger A, Böttcher B, Fiegl H, Marth C, Widschwendter A. Influence of Pregnancy-Related Conditions on Human Epididymis Protein 4 Serum Levels in Comparison to CA 125 - a Prospective Cohort Trial. Geburtshilfe Frauenheilkd 2021; 81:1047-1054. [PMID: 34531611 PMCID: PMC8437581 DOI: 10.1055/a-1475-4296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 04/05/2021] [Indexed: 11/17/2022] Open
Abstract
Introduction
HE4 and CA 125, two established biomarkers for assessing adnexal masses in non-pregnant women, are hardly investigated in pregnancy, especially in pregnancy-associated conditions. The aim was to evaluate HE4 and CA 125 levels in the course of pregnancy and to assess the impact of pregnancy disorders, contractions and rupture of membranes on HE4 and CA 125 serum levels in order to use these parameters for evaluation of adnexal masses in pregnancy.
Patients and Methods
Blood samples (n = 238) of 201 women seen at the Medical University of Innsbruck, Austria, were prospectively obtained during pregnancy and postpartum. Serum concentrations of HE4 and CA 125 were analyzed. ROMA index was calculated by the premenopausal formula.
Results
HE4 serum levels were highest in the third trimester. Contractions (p < 0.001), rupture of membranes (p = 0.005) and pregnancy-associated diseases (p = 0.003) were associated with higher HE4 levels. As much as 97.5% of HE4 measurements remained below the recommended cut-off for premenopausal women (70 pmol/l). CA 125 levels were not altered by pregnancy-associated conditions. Generally, CA 125 exhibited a wider serum level variability, exceeding the established cut-off of 35 U/ml in 16.4%.
Conclusions
HE4 serum levels are influenced by several pregnancy-related conditions leading to significantly higher levels in these cases. Despite differing medians according to trimester, the 95th percentile cut-offs and almost all maximum values during the entire course of pregnancy were below the established cut-off for premenopausal women. It was also superior to the performance of ROMA index. Therefore, HE4 can be used as a valuable negative predictive marker for the assessment of adnexal masses during pregnancy.
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Affiliation(s)
- Samira Abdel Azim
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Irene Mutz-Dehbalaie
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Verena Wieser
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Astrid Berger
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Bettina Böttcher
- Department of Gynecological Endocrinology and Reproductive Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Heidi Fiegl
- Department of Gynecology and Obstetrics, Laboratory for Clinical Biochemistry, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Marth
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Andreas Widschwendter
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
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El-Hamed ATA, Mahmoud SAA, Soliman AA, El-Yasergy DF. Immunohistochemical Expression of “HE4” in Endometrial Hyperplasia versus Endometrial Endometrioid Carcinoma. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.6189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Aim
Endometrial cancer is the most common cancer of the female genital tract. No effective biomarkers currently exist to allow for an efficient risk classification of endometrial carcinoma. Human epididymis protein 4 (HE4) overexpression is first observed in ovarian cancer tissue and subsequent research has shown that the HE4 overexpression has also been observed in patients with endometrial carcinoma. To our knowledge, this marker was evaluated in small number of research studies in cases of endometrial carcinoma versus hyperplasia. This has inspired us to test for immunohistochemical expression of HE4 in endometrial endometrioid carcinoma and hyperplastic endometria and to correlate HE4 expression with various prognostic pathological parameters including International Federation of Gynecology and Obstetrics (FIGO) grading and staging.
Methods
Immunohistochemical staining for HE4 was performed on paraffin-embedded sections of forty cases of endometrial endometrioid carcinoma and thirty cases of endometrial hyperplasia: including 15 cases of non-atypical hyperplasia and 15 cases of atypical hyperplasia. A histochemical score was used to evaluate HE4 expression by the tumor cells.
Results
In this study, HE4 overexpression level was significantly higher in endometrial endometrioid carcinoma than endometrial hyperplasia and significantly higher than non-atypical endometrial hyperplasia (P<0.05). HE4 strong expression was detected in 20% of atypical endometrial hyperplasia, but no statistical significance was detected between atypical hyperplasia and endometrial carcinoma. HE4 overexpression showed statistically significant positive correlation with FIGO grading, FIGO staging, and depth of myometrial invasion.
Conclusion:
During interpretation of endometrial biopsies of atypical hyperplasia, HE4 strong expression might raise the possibility of the presence of coexisting adenocarcinoma not biopsied or even warning of a near future malignant transformation. Also, strong expression of HE4 by tissue biopsy of adenocarcinoma should be reported as this might predict higher grade and stage of the tumor, a point that should be considered by surgeons while performing hysterectomy. These results should be further confirmed by extending the study on a large scale, correlation of HE4 expression with the molecular classification of Tumor Cancer Genome Atlas and long term follow up are required to establish the prognostic significance of HE4 expression in endometrial carcinoma and atypical hyperplasia.
Keywords: Endometrial carcinoma, Endometrial hyperplasia, HE4, Immunohistochemistry.
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Association of preoperative serum HE4 levels on the survival of patients with endometrial cancer. Arch Gynecol Obstet 2021; 304:1335-1343. [PMID: 34109467 DOI: 10.1007/s00404-021-06118-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 06/02/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE To evaluate the association between preoperative serum human epididymis protein 4 (HE4) levels and survival outcomes in endometrial cancer (EC) patients. METHODS A retrospective cohort study was conducted of EC patients who were scheduled for surgery between September 2013 and May 2014 at Rajavithi Hospital. Association between preoperative serum HE4 levels and clinicopathological characteristics were evaluated. Cox proportional-hazards model was used to compare overall survival (OS) and recurrence-free survival (RFS) between EC patients who had high serum HE4 levels and those who did not. RESULTS A total of 86 EC patients were enrolled. Serum HE4 levels was significantly associated with older age (p < 0.001), postmenopausal women (p = 0.001), large tumor size (p < 0.001), presence of lymphovascular invasion (p = 0.022), deep myometrial invasion (p = 0.001), lymph node metastasis (0.017), high-risk group (p < 0.001), and death status (p = 0.002). With a median follow-up of 53 months, the 3-years OS and PFS of EC patients who had high serum HE4 levels were significantly poorer than those who did not (71% vs 95.8%, and 67.7% vs 91.7%, respectively). A high serum HE4 level was a significant prognostic factor for OS and RFS from the univariate analysis. However, it was not a significant prognostic factor in the multivariate analysis. CONCLUSION Preoperative high serum HE4 levels were significantly associated with the worse clinicopathological characteristic of EC patients and decreased OS and RFS. Although there was no strong independent prognostic factor for survival, serum HE4 levels could be used in an algorithm for stratifying high-risk EC patients with more proper management.
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Özmen S, Kurt S, Ilgen O, Obuz FB, Sisman AR, Koyuncuoglu M. Comparison of MRI, CA-125 and HE-4 in determining the depth of myometrial invasion in cases with endometrial cancer. JOURNAL OF CLINICAL AND INVESTIGATIVE SURGERY 2021. [DOI: 10.25083/2559.5555/6.1.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Objective. Endometrial cancer is one of the most common malignancies in the world. There is no effective screening method used for predicting the clinical stage of the disease in the preoperative period and to plan the surgical procedure. The aim of this study is to compare the serum levels of CA-125 and HE-4 with MRI, to evaluate their ability to predict the depth of myometrial invasion in patients diagnosed with endometrial cancer, and to compare the specificity between these two tests. Materials and Methods. This prospective study was conducted at Dokuz Eylul University Faculty of Medicine, Department of Obstetrics and Gynecology, between February 2019 and February 2020. A total of 47 cases were included in the study. The cases were evaluated with MRI preoperatively to determine the extent of the disease. Preoperative serum CA-125 and HE-4 levels were measured by ELISA method and compared, and the superiority of the tests to each other in determining the depth of myometrial invasion was evaluated. Results. In patients with endometrioid cancer, preoperative CA-125 and HE-4 levels were found to be higher if the myometrial invasion is >50% and lymphovascular space invasion is positive, and the difference was statistically significant. A cut-off of 7,05 U/ml for CA-125 could detect the deeper myometrial invasion with a sensitivity of 83% and a specificity of 52%, respectively. A cut-off of 94,25 pmol/L for HE-4 could detect deeper myometrial invasion with a sensitivity of 75% and a specificity of 56%, respectively. The sensitivity of MRI in determining the depth of myometrial invasion was 87,1%, and the specificity was 86,7%. Conclusions. MRI, HE-4 and CA-125 were found to be valuable tests in predicting the extent of the disease and planning the surgical treatment. All three methods successfully predicted the myometrial invasion depth of the disease. The success rates of the tests in predicting the depth of myometrial invasion were MRI, HE-4 and CA-125, respectively. HE-4 and CA-125 could not reach the sensitivity and specificity of MRI in determining the depth of myometrial invasion at any cut-off value. However, it was proved in this study that they can play important roles as simpler and more cost-effective tests in determining the extent of the disease, able to contribute to surgical planning during preoperative evaluation.
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Can the Determination of HE4 and CA125 Markers Affect the Treatment of Patients with Endometrial Cancer? Diagnostics (Basel) 2021; 11:diagnostics11040626. [PMID: 33807168 PMCID: PMC8065496 DOI: 10.3390/diagnostics11040626] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/23/2021] [Accepted: 03/28/2021] [Indexed: 01/13/2023] Open
Abstract
The aim of our research was to determine the use of CA125 and HE4 as prognostic factors in patients with different clinical staging of endometrial cancer. Sixty-two patients with advanced endometrial cancer and 287 patients with early stage endometrial cancer participated in the study. Based on the results obtained in the study, the cut-off value for HE4 was established at 186 pmol/l and correlated with the possibility of cytoreductive surgery in patients with recurrent endometrial cancer. Univariate logistic regression revealed that serum concentrations for the median CA125 correlated with DFS (HR = 1.76, p = 0.033) and OS (HR = 1.42, p = 0.025), while the median of HE4 marker correlated with DFS (HR = 1.96, p = 0.015) and OS (HR = 1.83, p = 0.004). In the multivariate analysis, a decrease in CA125 level below normal range correlated positively with DFS and OS (HR = 1.45, p = 0.026; HR = 1.38, p = 0.037). HE4 levels correlated with DFS as follows: values below the normal range (HR = 2.31, p = 0.01), and with OS (HR = 1.89, p = 0.004). Based on the results obtained in the study, we found that HE4 is a sensitive tool for predicting the risk of recurrence and overall survival in patients with endometrial cancer.
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Rajadevan N, McNally O, Neesham D, Richards A, Naaman Y. Prognostic value of serum HE4 level in the management of endometrial cancer: A pilot study. Aust N Z J Obstet Gynaecol 2021; 61:284-289. [PMID: 33528032 DOI: 10.1111/ajo.13302] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 11/29/2020] [Indexed: 01/19/2023]
Abstract
BACKGROUND Human epididymis protein 4 (HE4) has shown promising utility as a prognostic biomarker in endometrial cancer. Increased serum HE4 levels may be associated with deeper myometrial invasion, extrauterine disease and poorer prognosis. AIM To evaluate the use of serum HE4 level, compared to and alongside other investigations, to accurately guide management in apparent early-stage endometrial cancer. MATERIALS AND METHODS This is a single-site prospective study of 100 patients with histologically confirmed endometrial cancer. All patients underwent preoperative measurements of HE4 and CA125 levels and a preoperative magnetic resonance imaging (MRI) to assess the depth of invasion, nodal status and tumour size. Correlation was sought between serum HE4 level, CA125 level, MRI findings and intra-operative frozen section with tumour type, grade and stage. RESULTS While both median HE4 and CA125 levels were higher with worsening clinicopathological features, serum HE4 level showed a more consistent association with high-risk features. Patients with a low-grade biopsy preoperatively and a low HE4 level (<70 pmol/L) demonstrated an 86.8% likelihood of having low-risk disease on final histopathology. In comparison, preoperative MRI or intraoperative frozen section alongside a low-grade biopsy demonstrated a similar likelihood of 86.2 and 87.7%, respectively. CONCLUSIONS When used in conjunction with an initial low-grade endometrial biopsy, serum HE4 level demonstrated a similar likelihood to both preoperative MRI and intraoperative frozen section in identifying low-risk disease on final histopathology. As a triaging tool this may be significant given that a preoperative, serum-based assay would likely be the least invasive, least resource-intensive and most cost-effective approach.
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Affiliation(s)
- Niveditha Rajadevan
- Department of Dysplasia and Oncology, Royal Women's Hospital, Melbourne, Victoria, Australia
| | - Orla McNally
- Department of Dysplasia and Oncology, Royal Women's Hospital, Melbourne, Victoria, Australia
| | - Deborah Neesham
- Department of Dysplasia and Oncology, Royal Women's Hospital, Melbourne, Victoria, Australia
| | - Anthony Richards
- Department of Dysplasia and Oncology, Royal Women's Hospital, Melbourne, Victoria, Australia
| | - Yael Naaman
- Department of Dysplasia and Oncology, Royal Women's Hospital, Melbourne, Victoria, Australia
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14
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The diagnostic value of human epididymis protein 4 for endometrial cancer is moderate. Sci Rep 2021; 11:575. [PMID: 33436780 PMCID: PMC7804086 DOI: 10.1038/s41598-020-79960-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 11/13/2020] [Indexed: 12/27/2022] Open
Abstract
Human epididymis protein 4 (HE4) has been used as a biomarker of endometrial cancer (EC) in clinical practice. However, there remains a lack of systemic research on the critical values of HE4 for diagnosing different clinical stages and pathological types of EC. This study investigated the accuracy of human epididymis protein 4 (HE4) in the diagnosis of EC. Patients who were hospitalized for a chief complaint of abnormal vaginal hemorrhage at Xinjiang Uyghur Autonomous Region People's Hospital between 2014 and 2019 were consecutively included. Pathological biopsy confirmed the diagnosis of EC; there were a total of 136 EC patients and 127 non-EC patients. The accuracy of HE4 in the diagnosis of EC was assessed with SPSS software. The accuracy of HE4 for diagnosing different clinical stages and pathological types of EC was also explored. The critical value of HE4 for endometrial cancer was 52.40 mmol/L, with a sensitivity of 57.35% and a specificity of 76.38%. For different stages of EC, the critical value was 36.9 mmol/L, and the sensitivity and specificity were 28% and 87.39%, respectively. For different pathological types, the critical value was 30.60 mmol/L, and the sensitivity and specificity were 93.85% and 33.33%, respectively. The diagnostic value of HE4 for EC is moderate, and the serum HE4 level cannot reflect the stage and type of EC.
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15
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Degez M, Caillon H, Chauviré-Drouard A, Leroy M, Lair D, Winer N, Thubert T, Dochez V. Endometrial cancer: A systematic review of HE4, REM and REM-B. Clin Chim Acta 2020; 515:27-36. [PMID: 33388311 DOI: 10.1016/j.cca.2020.12.029] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/24/2020] [Accepted: 12/28/2020] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Endometrial cancer, one of the most frequent pelvic gynecologic cancer worldwide, currently has no biomarker used to assess it in daily practice. Nonetheless, human epididymis 4 (HE4) appears to offer the best prospects, alone or combined with CA125. This study sought to systematically review the work on HE4 from the first publications in 2008 until now. MATERIAL AND METHODS Two independent reviewers searched the PubMed database with the terms "HE4″, "endometrial cancer", "endometrial carcinoma", and HE4 or human epididymis protein 4. Only original clinical research articles and meta-analyses, published in English, were included, with literature reviews and case reports excluded. RESULTS Studies were organized into 3 categories: diagnosis, prognosis, and recurrence/survival. Overall we identified 117 articles dealing with HE4 and endometrial cancer and selected 52 relevant texts: 46 articles, 6 meta-analyses. The sensitivity of HE4 for the diagnosis of endometrial cancer varied from 44.2% to 91% and its specificity from 65.5 to 100%, versus 24.1 to 71.5% and from 65.6 to 100% for CA125. Two meta-analyses of their combination produced areas under the curve (AUC): 0.83 and 0.86. Two available algorithms - the REM (risk of endometrial malignancy) and REM-B (risk of endometrial malignancy associated with BMI) scores - require more study. HE4 is also strongly associated with prognostic factors such as myometrial invasion, tumor grade, FIGO stage, and lymph node involvement. It also predicts recurrence and can serve as a monitoring tool, as reported by a 2018 meta-analysis with a hazard ratio of 2.15 (P < 0.001). CONCLUSION HE4, alone or associated with CA125, appears to be an important tool in the management of endometrial cancer, initially for diagnosis, but for assessing prognosis and survival. Other prospective and multicenter studies are necessary to confirm these hopes and be able to recommend the use of HE4 in regular practice.
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Affiliation(s)
- Manon Degez
- Service de Gynécologie-Obstétrique, CHU de Nantes, Nantes, France
| | | | | | - Maxime Leroy
- Plateforme de Biométries et Biostatistiques, CHU de Nantes, Nantes, France
| | - David Lair
- Département Promotion, Direction de la Recherche, CHU de Nantes, Nantes, France
| | - Norbert Winer
- Service de Gynécologie-Obstétrique, CHU de Nantes, Nantes, France; Centre d'Investigation Clinique (CIC), CHU de Nantes, Nantes, France
| | - Thibault Thubert
- Service de Gynécologie-Obstétrique, CHU de Nantes, Nantes, France; Centre d'Investigation Clinique (CIC), CHU de Nantes, Nantes, France
| | - Vincent Dochez
- Service de Gynécologie-Obstétrique, CHU de Nantes, Nantes, France; Centre d'Investigation Clinique (CIC), CHU de Nantes, Nantes, France.
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Espiau Romera A, Coronado Martín PJ, Chóliz Ezquerro M, Cuesta Guardiola T, Adiego Calvo I, Baquedano Mainar L. Value of preoperative HE4 as predictor of advanced disease in endometrioid endometrial cancer. Int J Gynaecol Obstet 2020; 153:64-70. [PMID: 33156532 DOI: 10.1002/ijgo.13473] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 09/06/2020] [Accepted: 11/05/2020] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To explore the predictive value of serum human epididymis protein 4 (HE4) marker in the preoperative prediction of the risk of advanced disease in the endometrioid subtype of endometrial cancer, and its association with poor prognostic factors. In addition, a cut-off value of HE4 was defined to classify patients according to these results. METHODS Prospective and multicenter cohort analytical pilot study of patients operated for endometrial cancer at the Miguel Servet University Hospital of Zaragoza (Spain) and the Complejo Universitario of León (Spain) from January 2017 to May 2019. Preoperative serum levels of HE4 were analyzed by clinical and pathologic characteristics. RESULTS In all, 126 patients were included. A statistically significant association was found between the preoperative HE4 value and node involvement (P = 0.008), late-stage disease (P = 0.003), high histologic grade (P = 0.007), deep myometrial invasion (P = 0.001), lymphovascular space invasion (P = 0.001), and other pathologic factors. In addition, an HE4 cut-off value (156.4 pmol/L) has been determined to predict, preoperatively, which patients will present with early stage disease. CONCLUSIONS The preoperative marker HE4 is a useful tool in the preoperative study of patients with endometrial cancer as it relates to late-stage disease as well as other prognostic factors in the endometrioid subtype of endometrial cancer.
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Affiliation(s)
- Andrea Espiau Romera
- Department of Obstetrics and Gynecology, Miguel Servet University Hospital, Zaragoza, Spain
| | | | - Marta Chóliz Ezquerro
- Department of Obstetrics and Gynecology, Miguel Servet University Hospital, Zaragoza, Spain
| | | | - Ignacio Adiego Calvo
- Department of Obstetrics and Gynecology, Miguel Servet University Hospital, Zaragoza, Spain
| | - Laura Baquedano Mainar
- Department of Obstetrics and Gynecology, Miguel Servet University Hospital, Zaragoza, Spain
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He Y, Wang J, Ma CX, Kang YH. Role of Human Epididymis Protein 4 (HE4) in Determining Survival of Patients With Endometrial Cancer: A Meta-Analysis. Technol Cancer Res Treat 2020; 19:1533033820971660. [PMID: 33148127 PMCID: PMC7653290 DOI: 10.1177/1533033820971660] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Human epididymis protein 4 (HE4) is a novel cancer biomarker. This study evaluates the prognostic role of HE4 in determining the survival of endometrial cancer patients. METHODS Literature search was conducted in electronic databases (Embase, Ovid, PubMed, Scopus, and Web of Science). Studies were selected if they reported the relationship between HE4 and the survival of endometrial cancer patients. Random-effects meta-analyses were performed to achieve estimates of baseline serum HE4 levels, the 5-year survival with high and low serum HE4 levels/expression, and the hazard ratios (HRs) of the survival between patients with high and low serum HE4 levels. RESULTS 9 studies (1404 patients; age 63.1 years [95% confidence interval (CI): 61.2, 64.9]; follow-up 35.9 months [95% CI: 32.2, 39.6]) were included. In these patients, serum HE4 levels were 83.36 picomole/liter (pM) [95% CI: 70.15, 96.56] overall but these were higher in patients with recurrence (108.13 pM [95% CI: 63.09, 153.18] and lower in patients with no recurrence (67.88 pM [95% CI: 65.09, 70.67]). The 5-year overall survival rate was higher in patients with low HE4 levels/expression (86% [95% CI: 79, 92] but lower in patients with high HE4 levels/expression (63% [95% CI: 58, 68]. A pooled HR of survival between patients with high and low serum HE4 levels of 2.25 [95% CI: 1.56, 2.94] indicated shorter survival in patients with high serum HE4 levels. CONCLUSION High HE4 concentrations in patients with endometrial cancer are found to be associated with shorter survival.
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Affiliation(s)
- Ying He
- Department of Gynecology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
| | - Jing Wang
- Department of Gynecology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
| | - Chun-Xing Ma
- Department of Gynecology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
| | - Yan-Hua Kang
- Department of Gynecology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China
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18
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Panyavaranant P, Manchana T. Preoperative markers for the prediction of high-risk features in endometrial cancer. World J Clin Oncol 2020; 11:378-388. [PMID: 32874951 PMCID: PMC7450819 DOI: 10.5306/wjco.v11.i6.378] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 05/11/2020] [Accepted: 06/03/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Preoperative evaluations aiming to assess high-risk features in clinical stage 1 endometrial cancer patients are crucial to refer these patients to gynecologic oncologists. Cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) have been reported in endometrial cancer patients with poor prognostic factors.
AIM To evaluate the association between preoperative levels of CA125 and HE4 and high-risk features and establish optimal cut-off values in clinical stage 1 endometrial cancer.
METHODS A retrospective study was conducted in clinical stage 1 endometrial cancer patients who underwent primary surgery between January 2013 and December 2018. A total of 128 patients had preoperative serum CA125 and HE4 measurements. High-risk features included grade 3 tumors, large tumor sizes (more than 2 cm), deep myometrial invasion (more than 50%), lymphovascular space invasion (LVSI), cervical involvement, extrauterine involvement and node metastasis. Receiver operating characteristic (ROC) curves were generated to analyze the optimal cut-off values.
RESULTS The mean age of the patients was 57.4 years, and 69.5% of them were postmenopausal. Most patients presented with stage I disease (67.2%) and had the endometrioid subtype (97.7%). The median CA125 and HE4 levels in all patients were 22.1 U/mL and 104.7 pmol/L, respectively. CA125 and HE4 levels were significantly elevated in those with large tumor sizes, deep myometrial invasion, LVSI, extrauterine metastasis, and advanced stage, but node metastasis was associated with elevated CA125 only. According to the ROC curve, both serum markers had statistical significance for the prediction of high-risk features only in postmenopausal patients, with an optimal cut-off value of 20 U/mL for CA125 [area under the concentration-time curve (AUC) = 0.72, P = 0.002] and 113 pmol/L for HE4 (AUC = 0.70, P = 0.006). The combination of both serum markers had 80% sensitivity and 64.4% positive predictive value. Significantly worse 5-year disease-free survival was observed in patients with high levels of CA125 and HE4 (78.4% and 100%, respectively; P = 0.01).
CONCLUSION Preoperative CA125 levels greater than 20 U/mL or HE4 levels greater than 113 pmol/L are associated with an increased risk of having high-risk features and present as prognostic factors in clinical stage 1 postmenopausal endometrial cancer patients. This information is helpful for general gynecologists to refer high-risk patients to gynecologic oncologists to perform complete surgical staging.
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Affiliation(s)
- Pinyada Panyavaranant
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Tarinee Manchana
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
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19
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Espiau Romera A, Cuesta Guardiola T, Benito Vielba M, De Bonrostro Torralba C, Coronado Martín PJ, Baquedano Mainar L. HE4 tumor marker as a predictive factor for lymphatic metastasis in endometrial cancer. Int J Gynaecol Obstet 2020; 149:265-268. [PMID: 32147821 DOI: 10.1002/ijgo.13140] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 02/04/2020] [Accepted: 03/05/2020] [Indexed: 12/24/2022]
Abstract
Endometrial cancer is the most common genital cancer in high-resource countries. Treatment is essentially surgical, but the role of lymphadenectomy in the treatment of low-stage and low-grade tumors has not been defined. Although no tumor factors have been validated for use as preoperative prognostic markers of endometrial cancer at yet, human epididymis protein 4 (HE4) has received much interest as a potential diagnostic and prognostic tumor marker. Since 2008, several studies have explored its utility in the management of endometrial cancer: HE4 may be a useful preoperative prognostic marker because it is associated with lymphatic metastasis and other unfavorable factors in endometrial cancer. In addition, some studies have explored a HE4 cutoff value to classify patients according to lymph node involvement. HE4 might be beneficial as a serum marker that helps clinicians in the decision-making algorithm for treatment of endometrial cancer, enabling them to perform individualized operations and decrease the adverse effects of unnecessary surgery.
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Affiliation(s)
| | | | - Marta Benito Vielba
- Department of Gynecology, Miguel Servet University Hospital, Zaragoza, Spain
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20
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Celik B, Bulut T, Yalcin AD. Tissue HE4 Expression Discriminates the Ovarian Serous Carcinoma but Not the Uterine Serous Carcinoma Patients. A New Adjunct to the Origin of the Tumor Site. Pathol Oncol Res 2020; 26:1145-1151. [PMID: 31165997 DOI: 10.1007/s12253-019-00675-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 05/23/2019] [Indexed: 02/05/2023]
Abstract
Both uterine serous carcinoma (USC) and ovarian serous carcinoma (OSC) are presented at advanced stage at the first admittion and dissseminated disease makes the anatomical site of the tumor origin imposible. CA125 and p53 are reliable markers that are useful for differentiating both uterine serous and ovarian serous carcinoma from their most common subtypes (endometrioid type carcinoma of ovary and uterus) but so far there is no histopathologic marker that differentiates USC from OSC. On the other hand, Trastuzumab (Herceptin) increases progression-free survival among USC patients, but not OSC patients and makes the histopathologically assigning the origin of the tumor important. So, the aim of this study was to evaluate the immunohistopathological discriminative value of the human epididymis secretory protein 4 (HE4) between OSC and USC patients. Patients with a diagnosis of OSC and UTC were enrolled. HE4 expression was evaluated by immunohistochemistry. The results were compared between groups. Of the tumor tissues studied, HE4 immunostaining was seen in the majority of ovarian serous carcinoma cases (89.65%), while endomatrial serous carcinoma cases were devoid of HE4 immunostaining. HE4 immunostaining was seen in 39.1% uterin serous carcinoma cases and this difference was statistically significant (p = 0.001). Our study demonstrated for the first time the potential of HE4 expression to predict the anatomical site of tumor origin. HE4 is a novel tumor marker that differentiates USC from OSC.
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Affiliation(s)
- Betul Celik
- Pathology Department, Health Science University, Antalya Hospital, Antalya, Turkey.
- Department of Pathology, Training Hospital, Varlik Mah, 07100, Antalya, Turkey.
| | - Tangul Bulut
- Pathology Department, Health Science University, Antalya Hospital, Antalya, Turkey
| | - Arzu Didem Yalcin
- Immunology Unit, Health Science University, Antalya Hospital, Antalya, Turkey
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21
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Behrouzi R, Ryan NAJ, Barr CE, Derbyshire AE, Wan YL, Maskell Z, Stocking K, Pemberton PW, Bolton J, McVey RJ, Crosbie EJ. Baseline Serum HE4 But Not Tissue HE4 Expression Predicts Response to the Levonorgestrel-Releasing Intrauterine System in Atypical Hyperplasia and Early Stage Endometrial Cancer. Cancers (Basel) 2020; 12:cancers12020276. [PMID: 31979212 PMCID: PMC7073190 DOI: 10.3390/cancers12020276] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/12/2020] [Accepted: 01/20/2020] [Indexed: 01/01/2023] Open
Abstract
The levonorgestrel-releasing intrauterine system (LNG-IUS) is a conservative management option for atypical hyperplasia (AH) and low grade early stage endometrial cancer (EEC), but around 1 in 3 patients fail to respond to treatment. The aim of this study was to investigate if serum and/or tissue HE4 expression could predict response to LNG-IUS therapy. Patients with AH or presumed Stage I EEC had serum and endometrial samples taken at baseline and at 3-month intervals over 12 months post-insertion of LNG-IUS. 74 patients were recruited and baseline demographics recorded. Of 57 patients for whom response was histologically determinable, 39 (68%) were responders and 18 (32%) non-responders. Mean baseline serum HE4 was significantly lower in responders (62.1 ± 1.1 pM, 95% confidence interval (CI) 52.7–73.2), compared to non-responders (125.6 ± 1.3 pM, 95% CI 74.5–211.7, p = 0.014), including when considering age, BMI, menopausal status, smoking status, and histological grade as covariables (p = 0.005). Baseline tissue HE4 expression was not significantly different in responders compared to non-responders (p = 0.999). Responders showed a significant mean reduction (−9.8 ± 3.4%, 95% CI −16.7 to −2.8%, p = 0.008) in serum HE4 between baseline and 3 months (p = 0.008), whereas non-responders showed no significant change (p = 0.676). Neither responders nor non-responders showed a significant percentage change in serum HE4 from baseline beyond 3 months (p > 0.05). Change in serum HE4 between baseline and 3 and 6 months and tissue HE4 tissue expression between baseline and 3, 6, and 12 months was not significantly different in responders compared to non-responders (p > 0.05). This study suggests that baseline serum HE4, but not baseline tissue HE4 expression, is independently predictive of response to the LNG-IUS and could be used to guide management decisions.
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Affiliation(s)
- Roya Behrouzi
- Department of Medicine, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK;
| | - Neil A. J. Ryan
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St. Mary’s Hospital, Manchester M13 9WL, UK; (N.A.J.R.); (Y.L.W.); (Z.M.)
| | - Chloe E. Barr
- Department of Obstetrics and Gynaecology, St. Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK; (C.E.B.); (A.E.D.)
| | - Abigail E. Derbyshire
- Department of Obstetrics and Gynaecology, St. Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK; (C.E.B.); (A.E.D.)
| | - Y. Louise Wan
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St. Mary’s Hospital, Manchester M13 9WL, UK; (N.A.J.R.); (Y.L.W.); (Z.M.)
| | - Zoe Maskell
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St. Mary’s Hospital, Manchester M13 9WL, UK; (N.A.J.R.); (Y.L.W.); (Z.M.)
| | - Katie Stocking
- Centre for Biostatistics, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester M13 9PL, UK;
| | - Philip W. Pemberton
- Department of Clinical Biochemistry, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK;
| | - James Bolton
- Department of Pathology, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK; (J.B.); (R.J.M.)
| | - Rhona J. McVey
- Department of Pathology, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK; (J.B.); (R.J.M.)
| | - Emma J. Crosbie
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St. Mary’s Hospital, Manchester M13 9WL, UK; (N.A.J.R.); (Y.L.W.); (Z.M.)
- Department of Obstetrics and Gynaecology, St. Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK; (C.E.B.); (A.E.D.)
- Correspondence:
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22
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Hernández JE, González-Montiel A, Allos-Villalva JCC, Cantú D, Barquet S, Olivares-Mundo A, Herrera LA, Prada D. Prognostic molecular biomarkers in endometrial cancer: A review. ACTA ACUST UNITED AC 2019; 7:17-28. [PMID: 34322276 PMCID: PMC8315102 DOI: 10.14312/2052-4994.2019-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Background: Endometrial cancer (EC) is the fourth most common malignancy in women worldwide and the most common gynecological cancer in developed countries. The endometrioid subtype has an excellent prognosis with conventional treatment; however, recurrence reduces overall survival. Objective: Describe the most relevant evidence regarding selected potential molecular biomarkers that may predict overall survival (OS), relapse-free survival (RFS), and cancer-specific survival (CSS) in EC. Methods: An exhaustive search was performed in PUBMED with the search terms endometrial cancer, molecular biomarker, and survival. We selected original articles written in English about endometrial cancer, molecular biomarkers, and that included survival analysis published between January 2000 and December 2016. Results: Several molecular prognostic biomarkers have been studied in terms of survival and therapeutic response in women with endometrial cancer; hormone receptors, microRNAs, and other molecules have emerged as potentially useful biomarkers, including HER2, p21, HE4, PTEN, p27, ANCCA, and ANXA2. Conclusions: The use of biomarkers in the assessment of OS, RFS, and CSS requires large trials to expand our understanding of endometrial carcinogenesis. Several molecular markers are significantly associated with a high tumor grade and advanced clinical stage in EC and, therefore, could have additive effects when combined.
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Affiliation(s)
- J Edgardo Hernández
- Unit of Biomedical Research, National Cancer Institute- Biomedical Research Institute, National Autonomous University of Mexico. San Fernando 22, Colonia Sección XVI, Delegatión Tlalpan, Mexico City, Mexico, 14080
| | - Ailyn González-Montiel
- Unit of Biomedical Research, National Cancer Institute- Biomedical Research Institute, National Autonomous University of Mexico. San Fernando 22, Colonia Sección XVI, Delegatión Tlalpan, Mexico City, Mexico, 14080
| | - Jesús C Ceb Allos-Villalva
- Department of Biomedical Informatics, Faculty of Medicine, National Autonomous University of Mexico, C.U., Av. Universidad 3000, Mexico City, Mexico, 04510
| | - David Cantú
- Unit of Biomedical Research, National Cancer Institute- Biomedical Research Institute, National Autonomous University of Mexico. San Fernando 22, Colonia Sección XVI, Delegatión Tlalpan, Mexico City, Mexico, 14080
| | - Salim Barquet
- Unit of Biomedical Research, National Cancer Institute- Biomedical Research Institute, National Autonomous University of Mexico. San Fernando 22, Colonia Sección XVI, Delegatión Tlalpan, Mexico City, Mexico, 14080
| | - Anny Olivares-Mundo
- Unit of Biomedical Research, National Cancer Institute- Biomedical Research Institute, National Autonomous University of Mexico. San Fernando 22, Colonia Sección XVI, Delegatión Tlalpan, Mexico City, Mexico, 14080
| | - Luis A Herrera
- Unit of Biomedical Research, National Cancer Institute- Biomedical Research Institute, National Autonomous University of Mexico. San Fernando 22, Colonia Sección XVI, Delegatión Tlalpan, Mexico City, Mexico, 14080
| | - Diddier Prada
- Unit of Biomedical Research, National Cancer Institute- Biomedical Research Institute, National Autonomous University of Mexico. San Fernando 22, Colonia Sección XVI, Delegatión Tlalpan, Mexico City, Mexico, 14080.,Department of Biomedical Informatics, Faculty of Medicine, National Autonomous University of Mexico, C.U., Av. Universidad 3000, Mexico City, Mexico, 04510
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Kumarasamy C, Madhav MR, Sabarimurugan S, Lakhotiya K, Pandey V, Priyadharshini T, Baxi S, Gothandam KM, Jayaraj R. Diagnostic and prognostic role of HE4 expression in multiple carcinomas: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2019; 98:e15336. [PMID: 31305389 PMCID: PMC6641664 DOI: 10.1097/md.0000000000015336] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Human epididymis protein 4 (HE4) protein has garnered a great degree of interest as a complementary biomarker to carbohydrate antigen 125 (CA125), or even as an independent biomarker for monitoring, diagnosis, and prognostication of ovarian cancer. Its use is currently limited to ovarian cancer. Recent studies have suggested that it could also be used in other types of cancers. METHODS The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines was used to design this meta-analysis protocol. The final study will also be conducted under the PRISMA guidelines for systematic reviews and meta-analyses. The core bibliographic database search will be carried out by 2 reviewers working individually, with each conducting an initial screening based on titles and abstracts. The shortlisted articles will be selected for review and statistical analysis based on predefined inclusion and exclusion criteria. Study characteristics, relevant clinicopathological characteristics and statistical data required for meta-analysis (hazard ratios [HRs] and 95% confidence interval [CIs) will be extracted and compiled into a MS Excel datasheet. Meta-analysis will be performed, using a random-effects model, and the results (pooled HR and 95% CI) will be presented in the form of a forest plot. Publication bias will also be assessed by use of Egger bias indicator test and funnel plot symmetry. If data are insufficient, a narrative line of review will be pursued. DISCUSSION HE4 protein has been shown to have great potential for clinical use as a diagnostic and prognostic marker in epithelial ovarian cancer (EOC). However, HE4 is not only limited to expression in ovarian cancer, but is also overexpressed in lung and endometrial cancers. The effectiveness of HE4 as a biomarker in cancers (other than EOC) has not yet been studied in the form of a comprehensive systematic review and meta-analysis. The results of this study should allow for expanded use of HE4 as a multiutility biomarker in multiple cancer types, thereby, elevating HE4's value as a cancer biomarker. PROSPERO REGISTRATION CRD42019120326.
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Affiliation(s)
- Chellan Kumarasamy
- University of Adelaide, North Terrace Campus, Adelaide South Australia, Australia
| | | | - Shanthi Sabarimurugan
- School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore
| | - Kartik Lakhotiya
- School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore
| | - Venkatesh Pandey
- School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore
| | - T Priyadharshini
- Department of Biochemistry, Bharathiyar University, Coimbatore, Tamil Nadu, India
| | | | - KM Gothandam
- School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore
| | - Rama Jayaraj
- College of Health and Human Sciences, Charles Darwin University, Ellengowan drive, Darwin, Australia
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24
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Karataş S, Şal V, Kahramanoğlu İ, Demirkıran F, Beşe T, Arvas M, Sofiyeva N, Güralp O, Uzun H. Ykl-40 and cancer antigen 72-4 as new and promising diagnostic and prognostic markers for endometrial cancer. Turk J Obstet Gynecol 2019; 15:235-242. [PMID: 30693139 PMCID: PMC6334238 DOI: 10.4274/tjod.77906] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 09/03/2018] [Indexed: 12/14/2022] Open
Abstract
Objective: To determine the predictive role of serum levels of YKL-40 and cancer antigen (CA) 72-4 in the diagnosis of endometrial cancer (EC). Materials and Methods: Forty-one patients with EC and 21 women with uterine polyps were evaluated between January and December 2015 in a prospective study. Results: Age, body mass index, preoperative serum YKL-40 and CA 72-4 levels were significantly higher in the malignant group compared with the control group. Serum YKL-40 levels were significantly higher in patients with superficial myometrial invasion and no lymph node involvement (p=0.042; p=0.004). No relationship between clinicopathologic factors and serum CA 72-4 levels was found. Conclusion: Serum CA 72-4 and YKL-40 levels are increased in women with EC compared with uterine polyps. Preoperative serum YKL-40 levels may be associated with favorable prognostic factors. The determination of YKL-40 before surgery may be helpful in the evaluation of the regional lymph nodes.
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Affiliation(s)
- Suat Karataş
- İstanbul Şişli Hamidiye Etfal Training and Research Hospital, Clinic of Obstetrics and Gynecology, İstanbul, Turkey
| | - Veysel Şal
- İstanbul Şişli Hamidiye Etfal Training and Research Hospital, Clinic of Obstetrics and Gynecology, İstanbul, Turkey
| | - İlker Kahramanoğlu
- İstanbul University Cerrahpaşa Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, İstanbul, Turkey
| | - Fuat Demirkıran
- İstanbul University Cerrahpaşa Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, İstanbul, Turkey
| | - Tugan Beşe
- İstanbul University Cerrahpaşa Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, İstanbul, Turkey
| | - Macit Arvas
- İstanbul University Cerrahpaşa Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, İstanbul, Turkey
| | - Nigar Sofiyeva
- Yale University Faculty of Medicine, Department of Obstetrics and Gynecology and Reproductive Sciences, New Haven, CT, USA
| | - Onur Güralp
- Klinikum Oldenburg University Hospital, Clinic of Obstetrics and Gynecology, Oldenburg, Germany
| | - Hafize Uzun
- İstanbul University Cerrahpaşa Faculty of Medicine, Department of Biochemistry, İstanbul,Turkey
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25
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Dai C, Zheng Y, Li Y, Tian T, Wang M, Xu P, Deng Y, Hao Q, Wu Y, Zhai Z, Dai Z, Lyu J. Prognostic values of HE4 expression in patients with cancer: a meta-analysis. Cancer Manag Res 2018; 10:4491-4500. [PMID: 30349381 PMCID: PMC6188164 DOI: 10.2147/cmar.s178345] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND To evaluate the prognostic impact of HE4 expression in patients with cancer. MATERIALS AND METHODS We searched the PubMed, Web of Science, Chinese National Knowledge Infrastructure and WangFang databases for publications concerning HE4 expression in patients with cancer. The correlation of HE4 expression level with overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) was analyzed. RESULTS In this meta-analysis, 29 studies, with a total of 4,235 patients, were included. Our results showed that HE4 expression was significantly associated with poorer OS (hazard ratio [HR] =2.15, 95% confidence interval [CI] =1.77-2.62, P<0.001). Further subgroup analysis found that this correlation was not affected by race (White: HR =1.92, 95% CI =1.53-2.39, P<0.001; Asian: HR =2.62, 95% CI =2.06-3.35, P<0.001) or tumor types (endometrial cancer: HR =2.91, 95% CI =1.86-4.53, P<0.001; ovarian cancer: HR =1.82, 95% CI =1.50-2.22, P<0.001; lung cancer: HR =2.31, 95% CI =1.54-3.47, P<0.001). Our meta-analysis showed that HE4 overexpression was significantly associated with DFS (HR =2.50, 95% CI =1.86-3.37, P<0.001) and PFS (HR =1.27, 95% CI =1.11-1.45, P=0.001). CONCLUSION These results suggest that expression of HE4 was associated with a worse prognosis in patients with cancer. HE4 is a potential novel prognostic factor in patients with cancer.
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Affiliation(s)
- Cong Dai
- Clinical Research Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China,
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, People's Republic of China,
| | - Yi Zheng
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, People's Republic of China,
| | - Yuanjie Li
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China
| | - Tian Tian
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, People's Republic of China,
| | - Meng Wang
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, People's Republic of China,
| | - Peng Xu
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, People's Republic of China,
| | - Yujiao Deng
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, People's Republic of China,
| | - Qian Hao
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, People's Republic of China,
| | - Ying Wu
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, People's Republic of China,
| | - Zhen Zhai
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, People's Republic of China,
| | - Zhijun Dai
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, People's Republic of China,
| | - Jun Lyu
- Clinical Research Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China,
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26
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Plotti F, Capriglione S, Scaletta G, Luvero D, Lopez S, Nastro FF, Terranova C, De Cicco Nardone C, Montera R, Angioli R. Implementing the Risk of Endometrial Malignancy Algorithm (REM) adding obesity as a predictive factor: Results of REM-B in a single-center survey. Eur J Obstet Gynecol Reprod Biol 2018; 225:51-56. [DOI: 10.1016/j.ejogrb.2018.03.044] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 03/17/2018] [Accepted: 03/22/2018] [Indexed: 01/05/2023]
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Abbink K, Zusterzeel PL, Geurts-Moespot AJ, Herwaarden AEV, Pijnenborg JM, Sweep FC, Massuger LF. HE4 is superior to CA125 in the detection of recurrent disease in high-risk endometrial cancer patients. Tumour Biol 2018; 40:1010428318757103. [PMID: 29463191 DOI: 10.1177/1010428318757103] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE To date, biomarkers are not routinely used in endometrial cancer diagnosis, prognosis, and follow-up. The purpose of this study was to evaluate whether serum HE4 was related to clinicopathological risk factors and outcome. Second, the role of serum HE4 and CA125 was assessed as indicator for recurrent disease during follow-up. METHODS A total of 174 patients with endometrial cancer between 1999 and 2009 were selected for this retrospective study. Serum HE4 and CA125 were analyzed at primary diagnosis, during follow-up, and at the time of recurrence. Correlations with clinicopathological factors were studied by univariate and multivariate survival analyses. Lead time was calculated in order to determine which serum marker was elevated prior to clinical detection of recurrent disease. RESULTS Serum levels of HE4 and CA125 were significantly associated with high tumor grade, myometrial invasion, lymph node involvement, and advanced stage (p < 0.01). HE4 was an independent prognostic factor for reduced disease-free survival and overall survival with hazard ratios of 2.96 (95% confidence interval: 1.18-7.99) and 3.27 (95% confidence interval: 1.18-9.02), respectively. At recurrence, 75% of the patients had an elevated HE4 compared to 54% with an elevated CA125. HE4 levels were more frequently elevated in patients with distant metastasis compared to local recurrences, 67% and 37%, respectively. Serum HE4 detected a recurrence with a median of 126 days earlier than clinical confirmation. CONCLUSION Elevated serum HE4 is an independent risk factor for reduced disease-free survival and overall survival. HE4 seems to be superior to CA125 in the detection of recurrent disease during follow-up, mainly in high-risk endometrial cancer patients who are more prone to distant metastasis.
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Affiliation(s)
- Karin Abbink
- 1 Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Petra Lm Zusterzeel
- 1 Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Anneke J Geurts-Moespot
- 2 Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | - Johanna Ma Pijnenborg
- 1 Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Fred Cgj Sweep
- 2 Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Leon Fag Massuger
- 1 Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
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Chovanec J, Selingerova I, Greplova K, Antonsen SL, Nalezinska M, Høgdall C, Høgdall E, Søgaard-Andersen E, Jochumsen KM, Fabian P, Valik D, Zdrazilova-Dubska L. Adjustment of serum HE4 to reduced glomerular filtration and its use in biomarker-based prediction of deep myometrial invasion in endometrial cancer. Oncotarget 2017; 8:108213-108222. [PMID: 29296235 PMCID: PMC5746137 DOI: 10.18632/oncotarget.22599] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 10/28/2017] [Indexed: 01/21/2023] Open
Abstract
Background We investigated the efficacy of circulating biomarkers together with histological grade and age to predict deep myometrial invasion (dMI) in endometrial cancer patients. Methods HE4ren was developed adjusting HE4 serum levels towards decreased glomerular filtration rate as quantified by the eGFR-EPI formula. Preoperative HE4, HE4ren, CA125, age, and grade were evaluated in the context of perioperative depth of myometrial invasion in endometrial cancer (EC) patients. Continuous and categorized models were developed by binary logistic regression for any-grade and for G1-or-G2 patients based on single-institution data from 120 EC patients and validated against multicentric data from 379 EC patients. Results In non-cancer individuals, serum HE4 levels increase log-linearly with reduced glomerular filtration of eGFR ≤ 90 ml/min/1.73 m2. HE4ren, adjusting HE4 serum levels to decreased eGFR, was calculated as follows: HE4ren = exp[ln(HE4) + 2.182 × (eGFR-90) × 10-2]. Serum HE4 but not HE4ren is correlated with age. Model with continuous HE4ren, age, and grade predicted dMI in G1-or-G2 EC patients with AUC = 0.833 and AUC = 0.715, respectively, in two validation sets. In a simplified categorical model for G1-or-G2 patients, risk factors were determined as grade 2, HE4ren ≥ 45 pmol/l, CA125 ≥ 35 U/ml, and age ≥ 60. Cumulation of weighted risk factors enabled classification of EC patients to low-risk or high-risk for dMI. Conclusions We have introduced the HE4ren formula, adjusting serum HE4 levels to reduced eGFR that enables quantification of time-dependent changes in HE4 production and elimination irrespective of age and renal function in women. Utilizing HE4ren improves performance of biomarker-based models for prediction of dMI in endometrial cancer patients.
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Affiliation(s)
- Josef Chovanec
- Clinic of Surgical Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.,Regional Centre of Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Iveta Selingerova
- Regional Centre of Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Kristina Greplova
- Regional Centre of Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.,Department of Laboratory Medicine, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Sofie Leisby Antonsen
- Gynecologic Clinic, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Monika Nalezinska
- Clinic of Surgical Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Claus Høgdall
- Gynecologic Clinic, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Estrid Høgdall
- Department of Pathology, Danish Cancer Biobank, Herlev University Hospital, Herlev, Denmark
| | - Erik Søgaard-Andersen
- Department of Gynecology and Obstetrics, Aalborg University Hospital, Aalborg, Denmark
| | - Kirsten M Jochumsen
- Department of Gynecology and Obstetrics, Odense University Hospital, Odense, Denmark
| | - Pavel Fabian
- Department of Oncological Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Dalibor Valik
- Regional Centre of Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.,Department of Laboratory Medicine, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Lenka Zdrazilova-Dubska
- Regional Centre of Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.,Department of Laboratory Medicine, Masaryk Memorial Cancer Institute, Brno, Czech Republic
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Bakrani M, Poor KS, Mehrzad V, Razmi N. Comparison of the Serum Level of Cancer Antigen 125 and Human Epididymis Protein 4 in Ovarian Cancer Patients and Healthy Groups in Isfahan City. Adv Biomed Res 2017; 6:124. [PMID: 29142887 PMCID: PMC5672644 DOI: 10.4103/2277-9175.216778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Background: Ovarian cancer is the most common fatal malignancy of the gynecology tract. The purpose of this study was to compare serum levels of tumor markers cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in both healthy groups and patients with ovarian cancer. Materials and Methods: this case–control study was performed on Seyed Al-Shohada Hospital in Isfahan. Research on the treatment of 44 patients with ovarian cancer and 44 healthy controls was performed. CA125 and HE4 were measured in serum by sandwich ELISA method. Results: Average CA125 in ovarian cancer patients (83.30 ± 43.99 μ/ml) was significantly higher than in healthy controls (12.39 ± 5.50 μ/ml) (P < 0.001). Average HE4 in ovarian cancer patients (295.41 ± 133.33 PM) was significantly higher than in healthy controls (114.64 ± 17.31 PM) (P < 0.001). Conclusions: HE4 test is complementary of CA125 test in women with epithelial ovarian cancer. It is also used to study the disease process.
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Affiliation(s)
- Mahnaz Bakrani
- Department of Biochemistry, Shiraz Sciences and Research Branch, Islamic Azad University, Shiraz, Isfahan, Iran
| | - Kahin Shahani Poor
- Department of Biochemistry, Falavarjan Branch, Islamic Azad University, Isfahan, Iran
| | - Valiollah Mehrzad
- Department of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nematallah Razmi
- Department of Biochemistry, Shiraz Sciences and Research Branch, Islamic Azad University, Shiraz, Isfahan, Iran
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Capriglione S, Luvero D, Plotti F, Terranova C, Montera R, Scaletta G, Schirò T, Rossini G, Benedetti Panici P, Angioli R. Ovarian cancer recurrence and early detection: may HE4 play a key role in this open challenge? A systematic review of literature. Med Oncol 2017; 34:164. [PMID: 28825178 DOI: 10.1007/s12032-017-1026-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 08/18/2017] [Indexed: 12/31/2022]
Abstract
Despite the improvement in overall survival for ovarian cancer (OC) patients, a fraction of patients with advanced-stage disease fails to respond to primary therapy and relapses in 70% of cases. For this reason, new predictive and monitoring tools are needed to identify OC recurrence and new biomarkers were studied, among which human epididymis 4 (HE4), primarily expressed in the reproductive and respiratory tracts, is one of the most promising, reporting a good sensitivity and specificity in detecting OC, overcoming the traditional role of carbohydrate antigen 125 (CA-125). In this review, we aim to discuss the latest evidence reported in the literature about the use of HE4 to monitor ovarian cancer treatment and to detect OC recurrence. We searched MEDLINE (PubMed), EMBASE, Cochrane Central Register of Controlled Trials, IBECS, BIOSIS, Web of Science, SCOPUS, congress abstracts, and Grey literature (Google Scholar; British Library) from January 1952 to June 2017. The search identified seven papers in line with eligibility criteria for this systematic review; all of them demonstrated a good performance of HE4 in OC recurrence. The challenge to anticipate the diagnosis of OC recurrence and to translate this early diagnosis of relapse in a survival and quality of life improvement is still open, and as reported in this review, HE4 may play a key role in this scenario. More studies are needed to validate and reinforce the role of HE4 in ovarian cancer recurrence and in its early detection.
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Affiliation(s)
- Stella Capriglione
- Department of Obstetrics and Gynaecology, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200 - 00128, Rome, Italy.
| | - Daniela Luvero
- Department of Obstetrics and Gynaecology, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200 - 00128, Rome, Italy
| | - Francesco Plotti
- Department of Obstetrics and Gynaecology, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200 - 00128, Rome, Italy
| | - Corrado Terranova
- Department of Obstetrics and Gynaecology, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200 - 00128, Rome, Italy
| | - Roberto Montera
- Department of Obstetrics and Gynaecology, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200 - 00128, Rome, Italy.,Unit of Obstetrics and Gynecology, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Giuseppe Scaletta
- Department of Obstetrics and Gynaecology, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200 - 00128, Rome, Italy
| | - Teresa Schirò
- Department of Obstetrics and Gynaecology, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200 - 00128, Rome, Italy
| | - Gianmarco Rossini
- Department of Obstetrics and Gynaecology, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200 - 00128, Rome, Italy
| | - Pierluigi Benedetti Panici
- Department of Gynecology Obstetrics and Urology, Policlinico Umberto I, ''Sapienza'' University of Rome, Rome, Italy
| | - Roberto Angioli
- Department of Obstetrics and Gynaecology, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200 - 00128, Rome, Italy
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Knific T, Osredkar J, Smrkolj Š, Tonin I, Vouk K, Blejec A, Frković Grazio S, Rižner TL. Novel algorithm including CA-125, HE4 and body mass index in the diagnosis of endometrial cancer. Gynecol Oncol 2017; 147:126-132. [PMID: 28735628 DOI: 10.1016/j.ygyno.2017.07.130] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 07/03/2017] [Accepted: 07/11/2017] [Indexed: 12/26/2022]
Abstract
OBJECTIVES To evaluate the diagnostic and prognostic potential of preoperative serum CA-125 and HE4 levels in patients with endometrial cancer. METHODS Prospective case-control study of 133 women who underwent surgical treatment at the University Medical Centre Ljubljana (64 patients with endometrial cancer, 69 control patients with prolapsed uterus or myoma). Serum CA-125 and HE4 levels were determined using electrochemiluminescent assays. RESULTS Serum CA-125 and HE4 levels were significantly higher in patients with endometrial cancer, compared to the controls (p=2.67×10-4, 1.36×10-7, respectively). A diagnostic model that combines serum CA-125 and HE4 levels and body mass index separated patients with endometrial cancer from controls, with AUC of 0.804, sensitivity of 66.7%, and specificity of 84.6%. Serum HE4 levels showed good prognostic potential and stratified the patients according to presence/absence of deep myometrial invasion (p=0.001) or lymphovascular invasion (p=0.003), with AUCs of 0.78 and 0.81, respectively. In low-risk patients with grade 1 and 2 endometrioid cancer for whom lymphadenectomy can be avoided, HE4 allowed stratification according to deep myometrial invasion (p=3.39×10-4), with AUC of 0.84. Although median HE4 levels were higher in patients with lymphovascular invasion, this difference did not reach significance (p=0.06). CONCLUSIONS A model based on preoperative serum CA-125 and HE4 levels and body mass index has good diagnostic accuracy for separation of patients with endometrial cancer and control patients. In patients with endometrial cancer, serum HE4 levels allow prediction of deep myometrial and lymphovascular invasion.
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Affiliation(s)
- Tamara Knific
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Joško Osredkar
- Clinical Institute of Clinical Chemistry and Biochemistry, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
| | - Špela Smrkolj
- Division of Obstetrics and Gynaecology, University Medical Centre, 1000 Ljubljana, Slovenia
| | - Irena Tonin
- Division of Obstetrics and Gynaecology, University Medical Centre, 1000 Ljubljana, Slovenia
| | - Katja Vouk
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Andrej Blejec
- National Institute of Biology, 1000 Ljubljana, Slovenia
| | - Snježana Frković Grazio
- Department of Pathology, Division of Obstetrics and Gynaecology, University Medical Centre, 1000 Ljubljana, Slovenia
| | - Tea Lanišnik Rižner
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia.
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Dewan R, Dewan A, Hare S, Bhardwaj M, Mehrotra K. Diagnostic Performance of Serum Human Epididymis Protein 4 in Endometrial Carcinoma: A Pilot Study. J Clin Diagn Res 2017; 11:XC01-XC05. [PMID: 28893024 DOI: 10.7860/jcdr/2017/28926.10285] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 05/19/2017] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Endometrial Cancer (EC) is a common female malignant disorder. To date, there are no specific tumour markers for EC that may be routinely used in clinical practice for diagnosis. AIM To evaluate the diagnostic performance of the serum Human Epididymis protein 4 (HE4) as biomarker for EC and to determine its association with clinicopathological variables. MATERIALS AND METHODS The study population included 60 postmenopausal women with a diagnosis of EC and 60 healthy postmenopausal female subjects (control group). Concentrations of serum HE4 and CA-125 in EC patients and control group were determined using Enzyme-Linked Immunosorbent Assays (ELISA). The value of serum HE4 and CA-125 for the diagnosis and prediction of stage, histology, myometrial invasion and lymph nodal metastasis was analysed. RESULTS The mean serum HE4 and CA-125 levels were significantly higher in patients with EC than those with control group (p<0.05). Comparison for HE4 and CA-125 between different stages showed a statistically significant difference. Stage I EC patients with <50% myometrial invasion had a significantly lower mean serum HE4 value than patients with >50% myometrial invasion (p=0.007). Corresponding values of CA-125 showed a similar trend (p=0.023). There were significantly higher levels of HE4 and CA-125 in cases with lymph node involvement. The levels of serum HE4 and CA-125 were higher in the non-endometroid histology, but the difference was not statistically significant. The Receiver Operating Characteristics (ROC) curve analysis for EC and control group showed that HE4 had greater Area Under Curve (AUC) when compared with CA-125. Using ROC curve, a serum HE4 concentration of 69.8 pmol/l (AUC 0.974) and/or serum CA-125 level of 34.50 U/mL (AUC 0.714) was used to predict malignancy. Sensitivity of combined biomarkers showed no additional improvement in comparison to HE4 or CA-125 alone. CONCLUSION Our results show that HE4 is a sensitive diagnostic serum marker for detection of EC patients, exhibiting a better diagnostic performance compared to CA-125. Good performance of HE4 in diagnosis of early stages EC indicates its usefulness as a prognostic marker and also to monitor therapy and detect early recurrence.
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Affiliation(s)
- Rupali Dewan
- Professor, Department of Obstetrics and Gynaecology, Vardhman Mahavir Medical College and Safdarjung Hospital, Delhi, India
| | - Abhinav Dewan
- Attending Consultant, Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
| | - Swati Hare
- Postgraduate Student, Department of Obstetrics and Gynaecology, Vardhman Mahavir Medical College and Safdarjung Hospital, Delhi, India
| | - Mausumi Bhardwaj
- Senior Scientist, Department of Research, National Institute of Cancer Prevention and Research, Noida, Uttar Pradesh, India
| | - Krati Mehrotra
- Medical Officer, Department of Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
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Plotti F, Scaletta G, Capriglione S, Montera R, Luvero D, Lopez S, Gatti A, De Cicco Nardone C, Terranova C, Angioli R. The Role of HE4, a Novel Biomarker, in Predicting Optimal Cytoreduction After Neoadjuvant Chemotherapy in Advanced Ovarian Cancer. Int J Gynecol Cancer 2017; 27:696-702. [PMID: 28406844 DOI: 10.1097/igc.0000000000000944] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVES This study aimed to evaluate serum human epididymis protein 4 (HE4) changes during neoadjuvant chemotherapy (NACT) to establish HE4 predebulking surgery cutoff values and to demonstrate that CA125, HE4, and computed tomography (CT) taken together are better able to predict complete cytoreduction after NACT in advanced ovarian cancer patients. METHODS From January 2006 to November 2015, patients affected by epithelial advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV), considered not optimally resectable, were included in this prospective study. After 3 cycles of NACT, all patients underwent debulking surgery and were allocated, according to residual tumor (RT), into group A (RT = 0) and group B (RT > 0). Serum CA125, HE4, and CT images were recorded during NACT and compared singularly and with each other in term of accuracy, sensitivity, specificity, and positive and negative predictive value. RESULTS A total of 94 and 20 patients were included in group A and group B, respectively. The HE4 values recorded before debulking surgery correlated with RT. The identified HE4 cutoff value of 226 pmol/L after NACT was able to classify patients at high or low risk of suboptimal surgery, with a sensitivity of 75% and a specificity of 85% (positive predictive value, 0.87; negative predictive value, 0.70). The combination of CA125, HE4, and CT imaging resulted in the best combination with a sensitivity of 96% and a specificity of 92% (positive predictive value, 0.96; negative predictive value, 0.94). CONCLUSIONS The novel biomarker HE4, in addition to CA125 and CT, is better able to predict the RT at debulking surgery and the prognosis of patients.
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Affiliation(s)
- Francesco Plotti
- *Department of Obstetrics and Gynaecology, Campus Bio-Medico University of Rome, Rome; and †Unit of Obstetrics and Gynecology, Magna Graecia University of Catanzaro, Catanzaro, Italy
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Serum HE4 is correlated to prognostic factors and survival in patients with endometrial cancer. Virchows Arch 2017; 470:655-664. [PMID: 28401338 DOI: 10.1007/s00428-017-2115-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 02/27/2017] [Accepted: 03/21/2017] [Indexed: 12/25/2022]
Abstract
The extent of surgery and the decision for adjuvant treatment in patients with endometrial cancer (EC) depend on the presence of risk factors for lymph node metastases and disease recurrence. Postoperative markers such as myometrial infiltration and specific mutations can select patients for adjuvant treatment but will not influence surgical planning. A biomarker stratifying patients into low-risk and high-risk groups before surgery could identify patients who benefit from more extensive surgery. Therefore, we evaluated the correlation of serum biomarker HE4 with clinical and recently identified prognostic pathological variables and survival. Patients treated for endometrial cancer between 1994 and 2014 were included. Serum HE4 concentration was measured in preoperatively obtained samples. A total of 88 patients were eligible for analysis. The majority (64%) was diagnosed with endometrioid-type adenocarcinoma. Serum HE4 concentration is significantly associated with stage of disease (p = 0.001), deep myometrial invasion (p < 0.001), exact depth of myometrial invasion (≥4 mm) (p = 0.01), tumour-free distance to serosa (≤7 mm) (p < 0.001), extensive lymph vascular space invasion (p = 0.04) and cervical involvement (p = 0.001). HE4 concentration and nodal involvement were correlated, although not significant (p = 0.17). Serum HE4 is an independent prognostic factor for recurrence-free survival (HR 5.12 per 10-fold increase in HE4, 95% CI 1.54-17.1) and overall survival (HR 7.48 per 10-fold increase in HE4, 95% CI 1.76-31.7). HE4 is a prognostic marker in endometrial cancer and is helpful in addition to other variables for the preoperative risk stratification of patients with endometrial cancer.
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Validation of REM score to predict endometrial cancer in patients with ultrasound endometrial abnormalities: results of a new independent dataset. Med Oncol 2017; 34:82. [DOI: 10.1007/s12032-017-0945-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 04/04/2017] [Indexed: 01/08/2023]
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Benati M, Montagnana M, Danese E, Paviati E, Giudici S, Ruzzenente O, Franchi M, Lippi G. The clinical significance of DJ-1 and HE4 in patients with endometrial cancer. J Clin Lab Anal 2017; 32. [PMID: 28374920 DOI: 10.1002/jcla.22223] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 03/05/2017] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The non-invasive diagnostic approach for early detection of endometrial cancer (EC) remains limited. To date, human epididymis protein 4 (HE4) has been intensively studied but its diagnostic is controversial in EC. DJ-1 is an oncoprotein secreted by cancer cells, recently identified as a potential diagnostic biomarker for breast cancer, melanoma, and pancreatic cancer. The aim of this study was to compare the diagnostic performances of DJ-1 and HE4 measured in EC patients and healthy controls (HC). METHODS Forty-five patients (63.9±12.0 years) with EC and 29 (63.2±13.3 years) HC were enrolled. Serum concentrations of DJ-1 and HE4 were measured using ELISA kits developed by R&D (Minneapolis, USA) and Fujirebio Diagnostic (Malvern, PA, USA), respectively. Differences between EC patients and HC were assessed by Mann-Whitney test and associations were tested by Spearman's correlation. The diagnostic performance was assessed using receiver operating characteristics (ROC) curves analysis. RESULTS Serum DJ-1 concentrations were found to be higher in EC patients than in HC (9533.6 vs 1988.5 pg/mL; P<.0001). The area under the ROC curve (ROC-AUC) was 0.95 (P<.0001). At the cut-off of 3654 pg/mL, the sensitivity and specificity were 0.89 and 0.90, respectively. HE4 serum levels were higher in EC patients than in HC (75.3 vs 56.2 pmol/L; P=.019), with an AUC of 0.66 (P=.020). The AUC obtained by the combination of the two markers resulted 0.96 (P<.0001). CONCLUSION These results suggest that increased serum DJ-1 levels are associated with EC and that this biomarker may be potentially useful for diagnosing EC.
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Affiliation(s)
- Marco Benati
- Department of Neurological, Biomedical and Movement Sciences, Clinical Biochemistry Section, University of Verona, Verona, Italy
| | - Martina Montagnana
- Department of Neurological, Biomedical and Movement Sciences, Clinical Biochemistry Section, University of Verona, Verona, Italy
| | - Elisa Danese
- Department of Neurological, Biomedical and Movement Sciences, Clinical Biochemistry Section, University of Verona, Verona, Italy
| | - Elisa Paviati
- Department of Neurological, Biomedical and Movement Sciences, Clinical Biochemistry Section, University of Verona, Verona, Italy
| | - Silvia Giudici
- Department of Surgery, Obstetrics and Gynaecology Section, University of Verona, Verona, Italy
| | - Orazio Ruzzenente
- Department of Neurological, Biomedical and Movement Sciences, Clinical Biochemistry Section, University of Verona, Verona, Italy
| | - Massimo Franchi
- Department of Surgery, Obstetrics and Gynaecology Section, University of Verona, Verona, Italy
| | - Giuseppe Lippi
- Department of Neurological, Biomedical and Movement Sciences, Clinical Biochemistry Section, University of Verona, Verona, Italy
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Prueksaritanond N, Cheanpracha P, Yanaranop M. Association of Serum HE4 with Primary Tumor Diameter and Depth of Myometrial Invasion in Endometrial Cancer Patients at Rajavithi Hospital. Asian Pac J Cancer Prev 2017; 17:1489-92. [PMID: 27039795 DOI: 10.7314/apjcp.2016.17.3.1489] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Although there are no biomarkers that are routinely used in endometrial cancer (EC) management, many studies have found that serum human epididymis protein 4 (HE4) is superior to cancer antigen 125 (CA125) in the detection of EC. The correlation of HE4 with two prognostic factors for EC, primary tumor diameter (PTD) and depth of myometrial invasion (DMI) may be useful in identifying EC patients at high risk of lymphatic dissemination. OBJECTIVE To evaluate the correlation of serum HE4 with PTD and DMI in patients with EC. MATERIALS AND METHODS A cross-sectional study was conducted on 70 EC patients who were scheduled for elective surgery at Rajavithi Hospital between 1st September 2013 and 30th May 2014. Preoperative serum levels of HE4 and CA125 were investigated, and then gross measurement of PTD was taken and postoperative pathologic slides were reviewed for DMI including histologic types, grading and staging. RESULTS Preoperative serum HE4 levels were strongly correlated with PTD (r=0.65, p<0.001) and moderately correlated with DMI (r=0.46, p<0.001). Moreover, serum HE4 levels were significantly elevated in EC patients with PTD >2 cm (p<0.001) and DMI > 50% (p=0.004). The performance of serum HE4 in identifying EC patients at low risk and high risk of lymph node metastasis was significantly better than that of CA125 (AUC 0.88 vs. 0.65, p=0.003). At an optimal cut-off value of 70 pM/L, serum HE4 had a sensitivity of 83.3% and a specificity of 80.0%. CONCLUSIONS In EC patients, preoperative serum HE4 is significantly correlated with PTD and DMI. Serum HE4 levels could be useful in identifying endometrial cancer patients at high risk of lymphatic spread who would benefit from systemic lymphadenectomy at the cut-off value of 70 pM/L.
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Affiliation(s)
- Nisa Prueksaritanond
- Department of Obstetrics and Gynecology, Rajavithi Hospital, Bangkok, Thailand E-mail :
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Yılmaz EPT, Kumtepe Y. Endometrial and Ovarian Cancer with MR Imaging Importance of Serum HE4 and CA 125 Levels in the Extent of Disease at Evaluation. Eurasian J Med 2017; 48:192-198. [PMID: 28149145 DOI: 10.5152/eurasianjmed.2016.0259] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVE Currently, no clinically useful tumor marker is available for primary diagnosis in endometrial cancer. Human epididymis protein-4 (HE-4) has high sensitivity and specificity as a tumor marker. Further, HE-4 has been shown to be elevated in early stage endometrial cancer and is more sensitive than CA 125. In our study, CA 125 and HE-4 reputation as a tumor marker for diagnosis of ovarian and endometrial cancer with the use of both the availability and affect the way we investigated the rate of diagnosis. MATERIALS AND METHODS Here 20 patients with ovarian cancer, 26 patients with endometrial cancer, which had been histologically diagnosed, and 40 healthy volunteers were included. Peripheral blood samples were taken and serum CA 125 and HE-4 were tested. RESULTS Serum CA 125 and HE-4 levels in patients with ovarian cancer were found to be significantly higher than those in healthy volunteers (p<0.05). Receiver-operating characteristic (ROC) analysis was performed. For patients with ovarian cancer and healthy controls, the CA 125 (0.83) and HE-4 (0.84) levels showed increased sensitivity (95%). There was no significant difference in the CA 125 levels in patients with endometrial cancer and healthy controls (p>0.05), whereas HE-4 levels were found to be higher in patients with endometrial cancer than in healthy controls (p<0.05). ROC analysis was performed. For endometrial cancer patients and healthy controls, the CA 125 (0.59) and HE-4 (0.63) levels showed increased sensitivity (88.5%). CONCLUSION In ovarian and endometrial cancer, wherein early diagnosis is the most important factor for prognosis and survival, HE-4 is a new serum tumor marker that can be used with the aim of noninvasive diagnoses. For early diagnosis, the concomitant use of CA 125 and HE-4 is more effective and reliable than using either of them alone.
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Affiliation(s)
| | - Yakup Kumtepe
- Department of Gynecology and Obstetrics, Atatürk University School of Medicine, Erzurum, Turkey
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Yılmaz SA, Altınkaya SÖ, Kerimoglu ÖS, Tazegül Pekin A, Akyürek F, Ilhan TT, Benzer N, Unlu A, Yuksel H, Celik C. The role of human epididymis secretory protein E4 in patients with endometrial cancer and premalignant endometrial lesions. J OBSTET GYNAECOL 2016; 37:58-63. [PMID: 28006994 DOI: 10.3109/01443615.2016.1174199] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We evaluated the concentrations of human epididymis secretory protein E4 (HE4) and Ca-125 in relation to clinicopathologic features in patients with endometrial cancer and premalignant endometrial lesions. Women with abnormal uterine bleeding (n = 167) who underwent endometrial sampling were divided into four groups. Group 1: endometrial cancer (n = 68), group 2: atypical endometrial hyperplasia (n = 12), group 3: endometrial hyperplasia without atypia (n = 39) and group 4: controls (n = 48). Women with endometrial cancer exhibited higher concentrations of HE4 levels than controls (91.4 pmol/L vs. 46.2 pmol/L, p < 0.001). HE4 levels were significantly higher in patients with lymphatic involvement, deep myometrial invasion, lymphovascular space involvement and non-endometrioid histology (p < 0.001). The sensitivity, specificity, positive and negative predictive values for HE4 in detecting endometrial cancer were 72.7%, 84.4%, 80% and 78.4%, respectively. Preoperative HE4 levels are more elevated in women with endometrial cancer than those with benign endometrium as well as in women with prognostic high-risk factors with endometrial cancer. HE4 may be used as an additional marker in combination with other clinicopathologic features for planning the treatment.
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Affiliation(s)
- Setenay Arzu Yılmaz
- a Department of Gynecology & Obstetrics , Selçuk University Faculty of Medicine , Konya , Turkey
| | - Sündüz Özlem Altınkaya
- b Department of Gynecology & Obstetrics , Faculty of Adnan Menderes University , Aydın , Turkey
| | - Özlem Seçilmiş Kerimoglu
- a Department of Gynecology & Obstetrics , Selçuk University Faculty of Medicine , Konya , Turkey
| | - Aybike Tazegül Pekin
- a Department of Gynecology & Obstetrics , Selçuk University Faculty of Medicine , Konya , Turkey
| | - Fikret Akyürek
- c Department of Biochemistry , Faculty of Selçuk University , Konya , Turkey
| | - Tolgay Tuyan Ilhan
- a Department of Gynecology & Obstetrics , Selçuk University Faculty of Medicine , Konya , Turkey
| | - Nilgün Benzer
- a Department of Gynecology & Obstetrics , Selçuk University Faculty of Medicine , Konya , Turkey
| | - Ali Unlu
- c Department of Biochemistry , Faculty of Selçuk University , Konya , Turkey
| | - Hasan Yuksel
- b Department of Gynecology & Obstetrics , Faculty of Adnan Menderes University , Aydın , Turkey
| | - Cetin Celik
- a Department of Gynecology & Obstetrics , Selçuk University Faculty of Medicine , Konya , Turkey
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Capriglione S, Plotti F, Miranda A, Lopez S, Scaletta G, Moncelli M, Luvero D, De Cicco Nardone C, Terranova C, Montera R, Angioli R. Further insight into prognostic factors in endometrial cancer: the new serum biomarker HE4. Expert Rev Anticancer Ther 2016; 17:9-18. [PMID: 27892774 DOI: 10.1080/14737140.2017.1266263] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Endometrial cancer (EC) is one of the most common gynecological cancer worldwide. To date, no good markers are routinely used in clinical practice for prognosis and monitoring. Areas covered: During the last years, an increasing interest in literature has been growing on HE4 (Human epididimis 4). Therefore, we aimed to gather all the evidence reported in literature analysing the potential prognostic value of HE4, compared to the well know tumor's features (histological type and grade, stage of disease, depth of myometrial invasion, lymphovascular space involvement and cervical involvement). Expert commentary: The analysis of data suggests that HE4 seems to have a good performance in prognosis and monitoring of the disease, helping to schedule the appropriste timing of imaging and surgery in a more individualized fashion. However, these findings surely require a validation in a larger cohorts of patients. Probably, in the next five years, prospective randomized trials will be performed to confirm the prognostic role of HE4 in EC and to find a tailored EC management strategy.
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Affiliation(s)
- Stella Capriglione
- a Department of Obstetrics and Gynaecology, Campus Bio Medico , University of Rome , Rome , Italy
| | - Francesco Plotti
- a Department of Obstetrics and Gynaecology, Campus Bio Medico , University of Rome , Rome , Italy
| | - Andrea Miranda
- a Department of Obstetrics and Gynaecology, Campus Bio Medico , University of Rome , Rome , Italy
| | - Salvatore Lopez
- a Department of Obstetrics and Gynaecology, Campus Bio Medico , University of Rome , Rome , Italy
| | - Giuseppe Scaletta
- a Department of Obstetrics and Gynaecology, Campus Bio Medico , University of Rome , Rome , Italy
| | - Michele Moncelli
- a Department of Obstetrics and Gynaecology, Campus Bio Medico , University of Rome , Rome , Italy
| | - Daniela Luvero
- a Department of Obstetrics and Gynaecology, Campus Bio Medico , University of Rome , Rome , Italy
| | - Carlo De Cicco Nardone
- a Department of Obstetrics and Gynaecology, Campus Bio Medico , University of Rome , Rome , Italy
| | - Corrado Terranova
- a Department of Obstetrics and Gynaecology, Campus Bio Medico , University of Rome , Rome , Italy
| | - Roberto Montera
- a Department of Obstetrics and Gynaecology, Campus Bio Medico , University of Rome , Rome , Italy
| | - Roberto Angioli
- a Department of Obstetrics and Gynaecology, Campus Bio Medico , University of Rome , Rome , Italy
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Rižner TL. Discovery of biomarkers for endometrial cancer: current status and prospects. Expert Rev Mol Diagn 2016; 16:1315-1336. [DOI: 10.1080/14737159.2016.1258302] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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The significance of markers in the diagnosis of endometrial cancer. MENOPAUSE REVIEW 2016; 15:176-185. [PMID: 27980530 PMCID: PMC5137482 DOI: 10.5114/pm.2016.63500] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 10/03/2016] [Indexed: 01/21/2023]
Abstract
Endometrial cancer is one of the most common cancers experienced by women throughout the world. It is also the most common malignancy within the female reproductive system, representing 37.7% of all disorders. The incidence increases with age, and is diagnosed most frequently in women between 45 and 65 years old. In the last few years, numerous studies have been performed to identify tumour biomarkers. Biomarkers include not only protein routinely used as tumour markers but also genes and chromosomes. The limiting factor in the use of markers in the diagnosis of endometrial cancer is their lack of specificity. However, specific markers for endometrial cancer are the subject of much research attention. Although moderately elevated levels of markers are present in a number of inflammatory or non-malignant diseases, significantly increased levels of markers indicate the development of cancer. Recently, research has been focused on the identification of molecular changes leading to different histological subtypes of endometrial cancer. In this paper the authors reviewed several currently investigated markers. Progress in these investigations is very important in the diagnostics and treatment of endometrial cancer. In particular, the identification of novel mutations and molecular profiles should enhance our ability to personalise adjuvant treatment with genome-guided targeted therapy.
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Wang Y, Han C, Teng F, Bai Z, Tian W, Xue F. Predictive value of serum HE4 and CA125 concentrations for lymphatic metastasis of endometrial cancer. Int J Gynaecol Obstet 2016; 136:58-63. [PMID: 28099710 DOI: 10.1002/ijgo.12010] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Revised: 08/01/2016] [Accepted: 10/10/2016] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To evaluate the predictive value of serum HE4 and CA125 concentrations in the preoperative prediction of risk of lymph node metastasis in endometrial cancer. METHODS A retrospective study was undertaken of data for patients with endometrial carcinoma treated surgically at a university hospital in China between August 2011 and December 2015. The preoperative serum levels of HE4 and CA125 were measured and analyzed by clinicopathologic characteristics. RESULTS Overall, 258 patients were included. The HE4 and CA125 concentrations were significantly elevated in patients with large lesions (≥2 cm), deep myometrial invasion (≥50%), an advanced disease stage, or lymph node metastasis (P<0.05 for all). HE4 concentrations also rose with age and histologic grade (P<0.01 for both). For lymph node metastasis, HE4 had higher sensitivity and negative predictive value than did CA125. The diagnostic performance of HE4 and CA125 in combination was superior to that of either marker alone. CONCLUSION The combined evaluation of serum HE4 and CA125 could provide gynecologic oncologists with improved information to guide the decision of whether to perform lymphadenectomy.
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Affiliation(s)
- Yingmei Wang
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Cha Han
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Fei Teng
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhaoyi Bai
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Wenyan Tian
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Fengxia Xue
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
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Ørbo A, Arnes M, Lyså LM, Borgfeldt C, Straume B. HE4 is a novel tissue marker for therapy response and progestin resistance in medium- and low-risk endometrial hyperplasia. Br J Cancer 2016; 115:725-30. [PMID: 27537387 PMCID: PMC5023780 DOI: 10.1038/bjc.2016.247] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 06/04/2016] [Accepted: 07/12/2016] [Indexed: 11/12/2022] Open
Abstract
Background: The aim of the present study was to investigate whether changes in the tissue expression of human epididymis-specific protein 4 (HE4) could predict therapy resistance and relapse after progestin hormone therapy for medium- and low-risk endometrial hyperplasia. Methods: Endometrial biopsies were obtained from women participating in a multicentre RCT performed according to the CONSORT guidelines; the women were randomly assigned to either LNG-IUS; 10 mg of oral medroxyprogesterone acetate (MPA) administered for 10 days per cycle; or 10 mg of oral MPA administered daily for 6 months. Of the 153 women who completed therapy, 141 had adequate material for immunohistochemistry in pre- and post-treatment biopsies. An antibody to HE4 (clone 12A2 monoclonal IgG1 antibody, Fujirebio Diagnostics, Inc.) was used for the immunohistochemical staining of the pre- and post-treatment biopsies from each participant. The expression of HE4 staining was evaluated by the histological score (H-score) using light microscopy. Results: Changes in the expression of HE4 (H-score) during therapy were related to the therapy group (P<0.001) and therapy response (P<0.001) of the individuals but could not predict relapse (P>0.05). Changes in the intracellular bodies were shown to predict both the therapy response (P=0.038) and relapse (P=0.014). Conclusions: Changes in the expression of HE4 during progestin therapy regimens can predict therapy response or indicate progestin resistance for medium- and low-risk endometrial hyperplasia.
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Affiliation(s)
- Anne Ørbo
- Department of Clinical Pathology, University Hospital of Tromsø, N-9038 Tromsø, Norway.,Research Group for Gynaecologic Oncology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway
| | - Marit Arnes
- Research Group for Gynaecologic Oncology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway
| | - Lena Myreng Lyså
- Department of Clinical Pathology, University Hospital of Tromsø, N-9038 Tromsø, Norway
| | - Christer Borgfeldt
- Department of Obstetrics and Gynecology, Skåne University Hospital, Lund, Sweden
| | - Bjørn Straume
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway
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Dobrzycka B, Mackowiak-Matejczyk B, Terlikowska KM, Kinalski M, Terlikowski SJ. Utility of HE4 to identify patients with endometrioid endometrial cancer who may require lymphadenectomy. Adv Med Sci 2016; 61:23-7. [PMID: 26344910 DOI: 10.1016/j.advms.2015.07.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 07/10/2015] [Accepted: 07/24/2015] [Indexed: 12/29/2022]
Abstract
PURPOSE The aim of the study was to establish whether preoperative serum levels of HE4 and CA125 could be a good predictor for lymphadenectomy in the early stage of endometrioid adenocarcinoma of the uterus. MATERIAL AND METHODS Preoperative serum HE4 and CA125 were measured in 78 postmenopausal patients treated surgically. The ROC curves were generated to determine the optimal cutoff values of HE4 and CA125 levels with optimum sensitivity and specificity for the prediction of lymphadenectomy. RESULTS Based on ROC curve, we found that the HE4 value of 78pmol/l is the best cutoff to identify candidates who may require lymphadenectomy with the sensitivity of 86.6% and the specificity of 67.2% (NPV=88.4% and PPV=51.2%). The area under the curve (AUC) equals 0.814 (95% CI=0.721-0.886). The cutoff level of CA125 that shows the prognostic indices is 26U/ml, with the sensitivity of 66.6% and the specificity of 61.2% (NPV=69.4% and PPV=44.3%). For CA125 the AUC amounts to 0.671 (95% CI=0.568-0.764). We also found a statistically significant difference, comparing HE4 and CA125 AUC (0.814 vs. 0.671, respectively, p<0.001). The combination of HE4 and CA125 established in our study as the cutoff point has the sensitivity of 81.2% and the specificity of 65.9% with NPV=83.4% and PPV=47.9%. CONCLUSIONS Our findings indicate that in the early stage of endometrioid endometrial cancer, HE4 can serve as a preoperative tool that can help to identify postmenopausal women who may require lymphadenectomy.
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Affiliation(s)
- Bozena Dobrzycka
- Department of Obstetrics, Gynecology and Maternity Care, Medical University of Bialystok, Bialystok, Poland
| | | | | | - Maciej Kinalski
- Department of Gynecology and Obstetrics, Provincial Hospital in Bialystok, Bialystok, Poland
| | - Slawomir Jerzy Terlikowski
- Department of Obstetrics, Gynecology and Maternity Care, Medical University of Bialystok, Bialystok, Poland.
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Colombo N, Creutzberg C, Amant F, Bosse T, González-Martín A, Ledermann J, Marth C, Nout R, Querleu D, Mirza MR, Sessa C. ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: Diagnosis, Treatment and Follow-up. Int J Gynecol Cancer 2016; 26:2-30. [PMID: 26645990 PMCID: PMC4679344 DOI: 10.1097/igc.0000000000000609] [Citation(s) in RCA: 476] [Impact Index Per Article: 52.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on 11-13 December 2014 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of endometrial cancer. Before the conference, the expert panel prepared three clinically-relevant questions about endometrial cancer relating to the following four areas: prevention and screening, surgery, adjuvant treatment and advanced and recurrent disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. Results of this consensus conference, together with a summary of evidence supporting each recommendation, are detailed in this article. All participants have approved this final article.
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Affiliation(s)
- Nicoletta Colombo
- *Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; †Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; ‡Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium and Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; §Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; ∥Medical Oncology Department, GEICO and MD Anderson Cancer Center, Madrid, Spain; ¶Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; #Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; **Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; ††Department of Surgery, Institut Bergonié, Bordeaux, France and Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Quebec, Canada; ‡‡Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and §§Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
| | - Carien Creutzberg
- *Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; †Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; ‡Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium and Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; §Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; ∥Medical Oncology Department, GEICO and MD Anderson Cancer Center, Madrid, Spain; ¶Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; #Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; **Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; ††Department of Surgery, Institut Bergonié, Bordeaux, France and Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Quebec, Canada; ‡‡Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and §§Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
| | - Frederic Amant
- *Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; †Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; ‡Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium and Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; §Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; ∥Medical Oncology Department, GEICO and MD Anderson Cancer Center, Madrid, Spain; ¶Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; #Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; **Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; ††Department of Surgery, Institut Bergonié, Bordeaux, France and Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Quebec, Canada; ‡‡Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and §§Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
| | - Tjalling Bosse
- *Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; †Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; ‡Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium and Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; §Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; ∥Medical Oncology Department, GEICO and MD Anderson Cancer Center, Madrid, Spain; ¶Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; #Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; **Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; ††Department of Surgery, Institut Bergonié, Bordeaux, France and Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Quebec, Canada; ‡‡Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and §§Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
| | - Antonio González-Martín
- *Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; †Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; ‡Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium and Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; §Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; ∥Medical Oncology Department, GEICO and MD Anderson Cancer Center, Madrid, Spain; ¶Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; #Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; **Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; ††Department of Surgery, Institut Bergonié, Bordeaux, France and Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Quebec, Canada; ‡‡Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and §§Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
| | - Jonathan Ledermann
- *Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; †Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; ‡Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium and Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; §Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; ∥Medical Oncology Department, GEICO and MD Anderson Cancer Center, Madrid, Spain; ¶Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; #Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; **Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; ††Department of Surgery, Institut Bergonié, Bordeaux, France and Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Quebec, Canada; ‡‡Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and §§Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
| | - Christian Marth
- *Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; †Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; ‡Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium and Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; §Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; ∥Medical Oncology Department, GEICO and MD Anderson Cancer Center, Madrid, Spain; ¶Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; #Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; **Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; ††Department of Surgery, Institut Bergonié, Bordeaux, France and Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Quebec, Canada; ‡‡Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and §§Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
| | - Remi Nout
- *Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; †Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; ‡Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium and Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; §Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; ∥Medical Oncology Department, GEICO and MD Anderson Cancer Center, Madrid, Spain; ¶Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; #Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; **Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; ††Department of Surgery, Institut Bergonié, Bordeaux, France and Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Quebec, Canada; ‡‡Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and §§Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
| | - Denis Querleu
- *Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; †Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; ‡Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium and Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; §Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; ∥Medical Oncology Department, GEICO and MD Anderson Cancer Center, Madrid, Spain; ¶Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; #Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; **Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; ††Department of Surgery, Institut Bergonié, Bordeaux, France and Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Quebec, Canada; ‡‡Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and §§Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
| | - Mansoor Raza Mirza
- *Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; †Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; ‡Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium and Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; §Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; ∥Medical Oncology Department, GEICO and MD Anderson Cancer Center, Madrid, Spain; ¶Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; #Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; **Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; ††Department of Surgery, Institut Bergonié, Bordeaux, France and Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Quebec, Canada; ‡‡Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and §§Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
| | - Cristiana Sessa
- *Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; †Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; ‡Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium and Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; §Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; ∥Medical Oncology Department, GEICO and MD Anderson Cancer Center, Madrid, Spain; ¶Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; #Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; **Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; ††Department of Surgery, Institut Bergonié, Bordeaux, France and Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Quebec, Canada; ‡‡Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and §§Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
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Electrochemical sandwich immunoassay for human epididymis-specific protein 4 using a screen-printed electrode modified with graphene sheets and gold nanoparticles, and applying a modular magnetic detector device produced by 3D laser sintering. Mikrochim Acta 2015. [DOI: 10.1007/s00604-015-1727-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Colombo N, Creutzberg C, Amant F, Bosse T, González-Martín A, Ledermann J, Marth C, Nout R, Querleu D, Mirza MR, Sessa C, Altundag O, Amant F, van Leeuwenhoek A, Banerjee S, Bosse T, Casado A, de Agustín L, Cibula D, Colombo N, Creutzberg C, del Campo JM, Emons G, Goffin F, González-Martín A, Greggi S, Haie-Meder C, Katsaros D, Kesic V, Kurzeder C, Lax S, Lécuru F, Ledermann J, Levy T, Lorusso D, Mäenpää J, Marth C, Matias-Guiu X, Morice P, Nijman H, Nout R, Powell M, Querleu D, Mirza M, Reed N, Rodolakis A, Salvesen H, Sehouli J, Sessa C, Taylor A, Westermann A, Zeimet A. ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: diagnosis, treatment and follow-up. Ann Oncol 2015; 27:16-41. [PMID: 26634381 DOI: 10.1093/annonc/mdv484] [Citation(s) in RCA: 775] [Impact Index Per Article: 77.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 10/05/2015] [Indexed: 12/27/2022] Open
Abstract
The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on 11-13 December 2014 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of endometrial cancer. Before the conference, the expert panel prepared three clinically relevant questions about endometrial cancer relating to the following four areas: prevention and screening, surgery, adjuvant treatment and advanced and recurrent disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. Results of this consensus conference, together with a summary of evidence supporting each recommendation, are detailed in this article. All participants have approved this final article.
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Affiliation(s)
- N Colombo
- Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy
| | - C Creutzberg
- Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - F Amant
- Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam
| | - T Bosse
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - A González-Martín
- Department of Medical Oncology, GEICO Cancer Center, Madrid Department of Medical Oncology, MD Anderson Cancer Center, Madrid, Spain
| | - J Ledermann
- Department of Oncology and Cancer Trials, UCL Cancer Institute, London, UK
| | - C Marth
- Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria
| | - R Nout
- Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands
| | - D Querleu
- Department of Surgery, Institut Bergonié, Bordeaux, France Department of Gynecology and Obstetrics, McGill University Health Centre, Montreal, Canada
| | - M R Mirza
- Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - C Sessa
- Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland
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ESMO–ESGO–ESTRO consensus conference on endometrial cancer: Diagnosis, treatment and follow-up. Radiother Oncol 2015; 117:559-81. [DOI: 10.1016/j.radonc.2015.11.013] [Citation(s) in RCA: 142] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 11/18/2015] [Indexed: 12/13/2022]
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Angioli R, Capriglione S, Scaletta G, Aloisi A, Miranda A, De Cicco Nardone C, Terranova C, Plotti F. The role of HE4 in endometrial cancer recurrence: how to choose the optimal follow-up program. Tumour Biol 2015; 37:4973-8. [PMID: 26531723 DOI: 10.1007/s13277-015-4324-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 10/26/2015] [Indexed: 12/30/2022] Open
Abstract
The aim of this study was to evaluate for the first time in the literature the role of HE4, at primary diagnosis, compared to CA125 as an indicator of endometrial cancer (EC) recurrence. Our study is a retrospective analysis of 252 EC patients treated, between January 2009 and July 2013, at the Division of Gynaecologic Oncology of Campus Bio-Medico University of Rome. Thirty-seven patients experienced recurrence. Median follow-up was 38 months. HE4 and CA125 levels were analyzed at primary diagnosis, during follow-up and either after histological or radiological confirmation of recurrent disease or at last registered visit, when patients returned to our Department with no evidence of recurrent disease. A statistically significant difference was observed between HE4 values at primary diagnosis and at recurrence, respectively, comparing recurrent and non-recurrent patients (p < 0.05), while CA125 values resulted not statistically significant (p = 0.08) at each time point. Considering the poor specificity of HE4 at threshold of 70 pmol/L at primary diagnosis, in our cohort of patients, we found out that HE4 cut-off of 201.3 pmol/L is able to correctly classify patients at high or low risk of EC recurrence, with a sensitivity of 80 % and a specificity of 91 % (PPV = 90.3 % and NPV = 90.8 %). In particular, HE4 performance improves in cases of endometrioid histotype. HE4 levels at primary diagnosis correlate with an increased risk of EC recurrence, particularly in cases of endometrioid histotype, and they may help to recognize patients who may need a more intensive follow-up.
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Affiliation(s)
- Roberto Angioli
- Department of Obstetrics, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200, 00128, Rome, Italy
| | - Stella Capriglione
- Department of Obstetrics, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200, 00128, Rome, Italy.
| | - Giuseppe Scaletta
- Department of Obstetrics, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200, 00128, Rome, Italy
| | - Alessia Aloisi
- Department of Obstetrics, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200, 00128, Rome, Italy
| | - Andrea Miranda
- Department of Obstetrics, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200, 00128, Rome, Italy
| | - Carlo De Cicco Nardone
- Department of Obstetrics, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200, 00128, Rome, Italy
| | - Corrado Terranova
- Department of Obstetrics, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200, 00128, Rome, Italy
| | - Francesco Plotti
- Department of Obstetrics, University of Rome "Campus Bio-Medico", Via Alvaro del Portillo, 200, 00128, Rome, Italy
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